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Wurzburg, Germany

The Julius Maximilians University of Würzburg is a public research university in Würzburg, Germany.The University of Wurzburg is one of the oldest institutions of higher learning in Germany having beenfounded in 1402. The University initially had a brief foundation and was closed in 1415, until it was permanently reopened in 1582 under the initiative of Julius Echter von Mespelbrunn. Today, the University is named for Julius Echter von Mespelbrunn and Maximilian Joseph.The University of Wurzburg is one of the leading universities in Germany being part of the U15 group of research-intensive German universities. The university is also a member of the distinguished Coimbra Group. Wikipedia.


Lueken U.,University of Wurzburg | Hahn T.,Goethe University Frankfurt
Current Opinion in Psychiatry | Year: 2016

Purpose of review The review provides an update of functional neuroimaging studies that identify neural processes underlying psychotherapy and predict outcomes following psychotherapeutic treatment in anxiety and depressive disorders. Following current developments in this field, studies were classified as 'mechanistic' or 'predictor' studies (i.e., informing neurobiological models about putative mechanisms versus aiming to provide predictive information). Recent findings Mechanistic evidence points toward a dual-process model of psychotherapy in anxiety disorders with abnormally increased limbic activation being decreased, while prefrontal activity is increased. Partly overlapping findings are reported for depression, albeit with a stronger focus on prefrontal activation following treatment. No studies directly comparing neural pathways of psychotherapy between anxiety and depression were detected. Consensus is accumulating for an overarching role of the anterior cingulate cortex in modulating treatment response across disorders. When aiming to quantify clinical utility, the need for single-subject predictions is increasingly recognized and predictions based on machine learning approaches show high translational potential. Summary Present findings encourage the search for predictors providing clinically meaningful information for single patients. However, independent validation as a crucial prerequisite for clinical use is still needed. Identifying nonresponders a priori creates the need for alternative treatment options that can be developed based on an improved understanding of those neural mechanisms underlying effective interventions. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Lassmann M.,University of Wurzburg | Nosske D.,Federal office for Radiation Protection
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2013

Purpose: 223Ra-Chloride (also called Alpharadin®) targets bone metastases with short range alpha particles. In recent years several clinical trials have been carried out showing, in particular, the safety and efficacy of palliation of painful bone metastases in patients with castration-resistant prostate cancer using 223Ra-chloride. The purpose of this work was to provide a comprehensive dosimetric calculation of organ doses after intravenous administration of 223Ra-chloride according to the present International Commission on Radiological Protection (ICRP) model for radium. Methods: Absorbed doses were calculated for 25 organs or tissues. Results: Bone endosteum and red bone marrow show the highest dose coefficients followed by liver, colon and intestines. After a treatment schedule of six intravenous injections with 0.05 MBq/kg of 223Ra-chloride each, corresponding to 21 MBq for a 70 kg patient, the absorbed alpha dose to the bone endosteal cells is about 16 Gy and the corresponding absorbed dose to the red bone marrow is approximately 1.5 Gy. Conclusion: The comprehensive list of dose coefficients presented in this work will assist in comparing and evaluating organ doses from various therapy modalities used in nuclear medicine and will provide a base for further development of patient-specific dosimetry. © 2012 Springer-Verlag Berlin Heidelberg.


Hiemke C.,University Medical Center Mainz | Pfuhlmann B.,University of Wurzburg
Handbook of Experimental Pharmacology | Year: 2012

As a consequence of individualized antipsychotic pharmacotherapy, many patients need more than a single drug, since they do not respond sufficiently to monotherapy. Other patients suffer from comorbid diseases and therefore require additional drugs from other pharmacological classes. Drug combinations, however, can give rise to pharmacokinetic and/or pharmacodynamic drug-drug interactions. Evaluation of pharmacokinetic interactions with antipsychotic drugs must consider substrate, inhibitor, and inducer properties for the cytochrome P450 (CYP) isoenzymes of all combined drugs. For consideration of pharmacodynamic interactions, special attention must be given to effects on dopamine D2, histamine H1, and acetylcholine M1 receptors and on cardiac potassium channels. Additive pharmacological actions of combined drugs on these target structures can induce adverse reactions such as extrapyramidal symptoms, drowsiness, metabolic disturbances leading to weight gain and cardiac problems, cognitive impairment, delirium, or ventricular arrhythmia. Measuring plasma concentrations, i.e., therapeutic drug monitoring (TDM), is valuable to adjust antipsychotic medication when drug combinations contain inhibitors or inducers that alter plasma concentrations of the antipsychotic drugs. Amalgamating the broad knowledge on drug-drug interactions and using appropriately the option to monitor plasma concentrations in blood will help to apply complex combination therapies with antipsychotic drugs with maximal efficiency and safety. © 2012 Springer-Verlag Berlin Heidelberg.


Cataract and glaucoma are both common comorbidities among older patients. Combining glaucoma surgery with minimal invasive phacoemulsification (phaco) is a considerable option to treat both conditions at the same time, although the combination with filtration surgery can produce a strong inflammatory response. Combined non-penetrating procedures like canaloplasty have shown to reduce intraocular pressure (IOP) comparable to trabeculectomy without the risk of serious bleb-related complications. The purpose of this retrospective study was to compare the outcomes of phacotrabeculectomy and phacocanaloplasty. Thirty-nine eyes with concomitant cataract and glaucoma who underwent phacotrabeculectomy (n=20; 51.3%) or phacocanaloplasty (n=19; 48.7%) were included into this trial on reduction of IOP, use of medication, success rate, incidence of complications and postsurgical interventions. Complete success was defined as IOP reduction by 30% or more and to 21 mmHg or less (definition 1a) or IOP to less than 18 mmHg (definition 2a) without glaucoma medication. Over a 12-month follow-up, baseline IOP significantly decreased from 30.0 ± 5.3 mmHg with a mean of 2.5 ± 1.2 glaucoma medications to 11.7 ± 3.5 mmHg with a mean of 0.2 ± 0.4 medications in eyes with phacotrabeculectomy (P< .0001). Eyes with phacocanaloplasty had a preoperative IOP of 28.3 ± 4.1 mmHg and were on 2.8 ± 1.1 IOP-lowering drugs. At 12 months, IOP significantly decreased to 12.6 ± 2.1 mmHg and less glaucoma medications were necessary (mean 1.0 ± 1.5 topical medications; P< .05). 15 patients (78.9%) with phacotrabeculectomy and 9 patients (60.0%) in the phacocanaloplasty group showed complete success according to definition 1 and 2 after 1 year (P= .276). Postsurgical complications were seen in 7 patients (36.8%) of the phacocanaloplasty group which included intraoperative macroperforation of the trabeculo-Descemet membrane (5.3%), hyphema (21.1%) and bleb formation (10.5%). Although more complications were observed in the phacotrabeculectomy group, no statistically significant difference was found. Phacocanaloplasty offers a new alternative to phacotrabeculectomy for treatment of concomitant glaucoma and cataract, although phacotrabeculectomy yielded in better results in terms of IOP maintained without glaucoma medications.


Tischler G.,University of Wurzburg
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2011

The wavelet tree is a compact data structure allowing fast rank, select, access and other queries on non binary sequences. It has many applications in indexed pattern matching and data compression. In contrast to applications of wavelet trees their construction has so far been paid little attention. In this paper we discuss time and space efficient algorithms for constructing wavelet trees. © 2011 Springer-Verlag.


Peck B.,Cancer Research UK Research Institute | Schulze A.,Cancer Research UK Research Institute | Schulze A.,University of Wurzburg
Cell Metabolism | Year: 2014

Tumors display distinct metabolic programs, and altered lipid metabolism is emerging as an important process in cancer. In this issue, Yue et al. (2014) report that aberrant cholesteryl ester accumulation is found in advanced prostate cancers with PTEN loss and PI3K/AKT activation. Importantly, inhibition of cholesterol esterification impaired cancer aggressiveness. © 2014 Elsevier Inc.


Barato A.C.,University of Wurzburg
Journal of Statistical Physics | Year: 2010

When a nonequilibrium growing interface in the presence of a wall is considered a nonequilibrium wetting transition may take place. This transition can be studied through Langevin equations or discrete growth models. In the first case, the Kardar-Parisi-Zhang equation, which defines a very robust universality class for nonequilibrium moving interfaces, with a soft-wall potential is considered. While in the second, microscopic models, in the corresponding universality class, with evaporation and deposition of particles in the presence of hard-wall are studied. Equilibrium wetting is related to a particular case of the problem, it corresponds to the Edwards-Wilkinson equation with a potential in the continuum approach or to the fulfillment of detailed balance in the microscopic models. In this review we present the analytical and numerical methods used to investigate the problem and the very rich behavior that is observed with them. © Springer Science+Business Media, LLC 2009.


P. hildebrandtiana Karsch, 1889 was relocated in the Taita Hills of Kenya. To present only the single female holotype was known. Male and female specimens of this species were found along forest edge in herbaceous vegetation in the Ngangao forest reserve. Closest relative of P. hildebrandtiana Karsch is P. uguenoensis Hemp restricted to the North and South Pare mountains. P. hildebrandtiana is re-described and the male newly described in this paper. Ecological information is provided and co-occurring Saltatoria species listed. Faunistic similarities in flightless Saltatoria between the Taita Hills and the South Pare mountains are discussed. Copyright © 2011, Magnolia Press.


Tessmer I.,University of Wurzburg | Melikishvili M.,University of Kentucky | Fried M.G.,University of Kentucky
Nucleic Acids Research | Year: 2012

O6-Alkylguanine-DNA alkyltransferase (AGT) repairs mutagenic O6-alkylguanine and O4-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 (∼0, ∼30 and ∼60°) that are consistent with models in which each protein induces a bend of ∼30°. 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. © 2012 The Author(s).


The number of periprosthetic fractures following hip replacement is increasing due to longer life expectancy and the rising number of joint replacements. The main causes of periprosthetic fractures include trauma, implant specific factors or loosening of the endoprosthesis. When planning therapy, surgeons should consider specific and general implant- and patient-related risk factors to ensure the best possible treatment. Established classification systems can facilitate preoperative planning. At present, the Vancouver classification system probably comes closest to the ideal, as it considers fracture configuration, stability of the implant and quality of the bone stock. Depending on these factors, therapeutic options include conservative treatment, fracture stabilisation or replacement of the endoprosthesis. The problems associated with periprosthetic fractures of varying etiology and the available treatment options are discussed against the background of the established classification systems.


Goldman D.,U.S. National Institutes of Health | Domschke K.,University of Wurzburg
International Journal of Neuropsychopharmacology | Year: 2014

This review, the first of an occasional series, tries to make sense of the concepts and uses of deep sequencing of polynucleic acids (DNA and RNA). Deep sequencing, synonymous with next-generation sequencing, high-throughput sequencing and massively parallel sequencing, includes whole genome sequencing but is more often and diversely applied to specific parts of the genome captured in different ways, for example the highly expressed portion of the genome known as the exome and portions of the genome that are epigenetically marked either by DNA methylation, the binding of proteins including histones, or that are in different configurations and thus more or less accessible to enzymes that cleave DNA. Deep sequencing of RNA (RNASeq) reverse-transcribed to complementary DNA is invaluable for measuring RNA expression and detecting changes in RNA structure. Important concepts in deep sequencing include the length and depth of sequence reads, mapping and assembly of reads, sequencing error, haplotypes, and the propensity of deep sequencing, as with other types of 'big data', to generate large numbers of errors, requiring monitoring for methodologic biases and strategies for replication and validation. Deep sequencing yields a unique genetic fingerprint that can be used to identify a person, and a trove of predictors of genetic medical diseases. Deep sequencing to identify epigenetic events including changes in DNA methylation and RNA expression can reveal the history and impact of environmental exposures. Because of the power of sequencing to identify and deliver biomedically significant information about a person and their blood relatives, it creates ethical dilemmas and practical challenges in research and clinical care, for example the decision and procedures to report incidental findings that will increasingly and frequently be discovered. © CINP 2014.


Helfrich-Forster C.,University of Wurzburg
Journal of Neurogenetics | Year: 2014

This paper is dedicated to Karl-Friedrich Fischbach, who has always shared with me the interest in the function of the fly brain, especially that of its optic lobes. He has accompanied me during my first steps in scientific research. The paper tells the story how our first common attempts to localize the circadian clock in the fly brain finally helped in phrasing the two-oscillator principle of circadian clocks that seems to be valid far beyond the fly circadian system. I hope that Karl-Friedrich will take this story as praise for his generosity in supporting younger scientists outside his own lab, even without the reward of a common paper. © 2014 Informa Healthcare USA, Inc.


Schenkel A.,University of Wurzburg
General Relativity and Gravitation | Year: 2011

We study the quantum field theory (QFT) of a free, real, massless and curvature coupled scalar field on self-similar symmetric spacetimes, which are deformed by an abelian Drinfel'd twist constructed from a Killing and a homothetic Killing vector field. In contrast to deformations solely by Killing vector fields, such as the Moyal-Weyl Minkowski spacetime, the equation of motion and Green's operators are deformed. We show that there is a *-algebra isomorphism between the QFT on the deformed and the formal power series extension of the QFT on the undeformed spacetime. We study the convergent implementation of our deformations for toy-models. For these models it is found that there is a *-isomorphism between the deformed Weyl algebra and a reduced undeformed Weyl algebra, where certain strongly localized observables are excluded. Thus, our models realize the intuitive physical picture that noncommutative geometry prevents arbitrary localization in spacetime. © 2011 Springer Science+Business Media, LLC.


Bluthgen N.,University of Wurzburg
Basic and Applied Ecology | Year: 2010

Network analyses of mutualistic or antagonistic interactions between species are very popular, but their biological interpretations are often unclear and incautious. Here I propose to distinguish two possible implications of network patterns in conjunction with solutions to avoid misinterpretations. Interpretations can be either(1)niche-based, describing specialisation, trait (mis-)matching between species, niche breadth and niche overlap and their relationship to interspecific competition and species coexistence, or(2)impact-based, focusing on frequencies of interactions between species such as predation or infection rates and mutualistic services, aiming to quantify each species' relative contribution to an ecological effect. For niche-based implications, it is crucial to acknowledge the sampling limitations of a network and thus control for the number of observations of each species. This is particularly important for those kinds of networks that summarise observed interactions in communities (e.g. bipartite host-parasitoid or plant-animal networks), rather than compile information from different sources or experiments (as in many food webs). Variation in total observation frequencies may alone explain network patterns that have often been interpreted as 'specialisation asymmetries' (nestedness, dependence asymmetries). I show analytically that 'dependence asymmetries' between two species (or two guilds) only reflect variation in their total observation frequencies. To depict true asymmetries in niche breadth, independent data are required for both species. Moreover, simulated co-extinction scenarios assume that each species 'depends' on its associated partners in the network (again niche-based), but species that appear most endangered are simply those with one or very few observations and are not necessarily specialised. Distinguishing niche-based and impact-based interpretations may help to bridge terminological and conceptual gaps between network pattern analyses and traditional community ecology. © 2010 Gesellschaft für Ökologie.


Garcia S.B.,University of Sao Paulo | Stopper H.,University of Wurzburg | Kannen V.,University of Sao Paulo
Cellular and Molecular Life Sciences | Year: 2014

Several different cell types constitute the intestinal wall and interact in different manners to maintain tissue homeostasis. Elegant reports have explored these physiological cellular interactions revealing that glial cells and neurons not only modulate peristalsis and mechanical stimulus in the intestines but also control epithelial proliferation and sub-epithelial angiogenesis. Although colon carcinoma arises from epithelial cells, different sub-epithelial cell phenotypes are known to support the manifestation and development of tumors from their early steps on. Therefore, new perspectives in cancer research have been proposed, in which neurons and glial cells not only lead to higher cancer cell proliferation at the tumor invasion front but also further enhance angiogenesis and neurogenesis in tumors. Transformation of physiological neural activity into a pro-cancer event is thus discussed for colon carcinogenesis herein. © 2014 Springer.


Mehta P.,Raman Research Institute | Winter W.,University of Wurzburg
Journal of Cosmology and Astroparticle Physics | Year: 2011

We discuss the importance of flavor ratio measurements in neutrino telescopes, such as by measuring the ratio between muon tracks to cascades, for the purpose of extracting new physics signals encountered by astrophysical neutrinos during propagation from the source to the detector. The detected flavor ratios not only carry the energy information of specific new physics scenarios which alter the transition probabilities in distinctive ways, but also the energy dependent flavor composition at the source. In the present work, we discuss the interplay of these two energy dependent effects and identify which new physics scenarios can be distinguished from the detected flavor ratios as a function of astrophysical parameters. We use a recently developed self-consistent neutrino production model as our toy model to generate energy dependent source flavor ratios and discuss (invisible) neutrino decay and quantum decoherence as specific new physics examples. Furthermore, we identify potentially interesting classes of sources on the Hillas plot for the purpose of new physics searches. We find that sources with substantial magnetic fields 103Gauss≲B≲106Gauss, such as Active Galactic Nuclei (AGN) cores, white dwarfs, or maybe gamma-ray bursts, have, in principle, the best discrimination power for the considered new physics scenarios, whereas AGN jets, which typically perform as pion beam sources, can only discriminate few sub cases in the new physics effects. The optimal parameter region somewhat depends on the class of new physics effect considered. © 2011 IOP Publishing Ltd and SISSA.


Papenfort K.,Princeton University | Vogel J.,University of Wurzburg
Frontiers in cellular and infection microbiology | Year: 2014

Enteric pathogens often cycle between virulent and saprophytic lifestyles. To endure these frequent changes in nutrient availability and composition bacteria possess an arsenal of regulatory and metabolic genes allowing rapid adaptation and high flexibility. While numerous proteins have been characterized with regard to metabolic control in pathogenic bacteria, small non-coding RNAs have emerged as additional regulators of metabolism. Recent advances in sequencing technology have vastly increased the number of candidate regulatory RNAs and several of them have been found to act at the interface of bacterial metabolism and virulence factor expression. Importantly, studying these riboregulators has not only provided insight into their metabolic control functions but also revealed new mechanisms of post-transcriptional gene control. This review will focus on the recent advances in this area of host-microbe interaction and discuss how regulatory small RNAs may help coordinate metabolism and virulence of enteric pathogens.


Joshi J.C.,Raman Research Institute | Winter W.,University of Wurzburg | Gupta N.,Raman Research Institute
Monthly Notices of the Royal Astronomical Society | Year: 2014

Cosmic rays diffuse through the interstellar medium and interact with matter and radiations as long as they are trapped in the Galactic magnetic field. The IceCube experiment has detected some TeV-PeV neutrino events whose origin is yet unknown. We study if all or a fraction of these events can be described by the interactions of cosmic rays with matter. We consider the average target density needed to explain them for different halo sizes and shapes, the effect of the chemical composition of the cosmic rays, the impact of the directional information of the neutrino events, and the constraints from gamma-ray bounds and their direction. We do not require knowledge of the cosmic ray escape time or injection for our approach. We find that, given all constraints, at most 0.1 of the observed neutrino events in IceCube can be described by cosmic ray interactions with matter. In addition, we demonstrate that the currently established chemical composition of the cosmic rays contradicts a peak of the neutrino spectrum at PeV energies. ©2014 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.


Monoranu C.M.,University of Wurzburg
Current Alzheimer research | Year: 2013

Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage and increase with age. To unravel the impact of mtDNA damage on AD development, we analyzed mtDNA deletion levels in diverse neuronal cell types of four brain regions (hippocampal CA1 and CA2 regions, nucleus tractus spinalis nervi trigemini, and the cerebellum) that exhibit differing levels of vulnerability to AD related changes at progressive Braak stages compared with age-matched controls. Neurons from these four brain regions were collected using laser microdissection, and analyzed using quantitative polymerase chain reaction (qPCR). Although, no correlation between mtDNA deletion levels and AD progression were found, the data revealed regional and cell type specific selective vulnerability towards mtDNA deletion levels. In conclusion, unexpected results were obtained as granule cells from the cerebellum and neurons from the nucleus tractus spinalis nervi trigemini of the brain stem displayed significant higher mtDNA deletion levels than pyramidal cells from hippocampal CA1 and CA2 region in age and AD.


Buttmann M.,University of Wurzburg
Expert Review of Neurotherapeutics | Year: 2010

Treating multiple sclerosis (MS) with monoclonal antibodies (mAbs) has been marked by both progress and setbacks in the past 2 years, which are reviewed here. The natalizumab section of the article centers around progressive multifocal leukoencephalopathy (PML), and discusses PML risk in relation to treatment duration, bioassays for individual risk prediction, the concept of drug holidays, clinical course and treatment of PML, as well as safety-related regulatory actions. The rituximab section critically analyzes recent clinical trial results, discusses the clinical relevance of anti-idiotypic mAbs and makes a short excursion to neuromyelitis optica. Following this, the newer anti-CD20 mAbs ocrelizumab and ofatumumab, which are currently being tested in Phase II for MS, are reviewed and compared. The alemtuzumab section highlights novel data on mechanisms of action, potentially allowing individual risk prediction, and new results from the CAMMS223 trial, as well as the current status of the pivotal MS studies. The daclizumab section summarizes new open-label data, shedding more light on the adverse-effect profile of the drug in MS patients, and reports on its Phase III status. Subsequently, a failed ustekinumab trial and LY2127399 are reviewed. Taking into account late Phase II and III data on novel oral agents, the final section attempts to provide a detailed perspective on disease-modifying MS therapy in the medium term. © 2010 Expert Reviews Ltd.


Kneisel C.,University of Wurzburg
Geomorphology | Year: 2010

Frozen ground conditions and the geomorphological significance of contemporary permafrost have been assessed in a mountain environment south of Abisko, Sweden, using a combination of different methods including geomorphological mapping, near-surface temperature monitoring and 2D near-surface geophysics. The results confirm the existence of permafrost and related periglacial morphodynamics (e.g. gelifluction) for most of the upper parts of the investigation area (above 1200. m. a.s.l.). The middle parts form a transition zone with periglacial morphodynamics related to perennial and seasonal frost (gelifluction/solifluction) in combination with presently inactive periglacial landforms (ca. 1100 to 1200. m. a.s.l.). At lower altitudes recent morphodynamics are not related to contemporary permafrost conditions although landforms indicating the former impact of permafrost are present. The permafrost distribution is heterogeneous, showing a strong relationship to the distribution and duration of snow cover and surface textural characteristics. These factors together with the local hydrological conditions also determine the characteristics of the frozen ground. Multiple 2D electrical resistivity imaging surveys pointed to highly variable subsurface resistivity patterns corresponding to different frozen ground characteristics at close distance. © 2009 Elsevier B.V.


Faller H.,University of Wurzburg
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | Year: 2012

As a result of increasing demands for more patient-centeredness in the German health care system, physician-patient communication has been subject to transformation. Physicians are being requested to take into account their patients' communicative needs, including information, shared decision making, and emotional support, more vigorously than they had been in the past. A cooperative model of the physician-patient relationship is considered most suitable for fulfilling these needs and for empowering patients to make informed decisions regarding their own health care. However, a large body of evidence exists-particularly regarding communication between cancer patients and their doctors-that shows that patients' needs are not adequately addressed or met. This potential for optimization is all the more important because targeting patients' needs during doctor-patient communication not only improves patients' satisfaction with the communication, quality of life, and well-being, but may also produce better treatment outcomes. © Springer-Verlag 2012.


Fischbach W.,University of Wurzburg
Digestive Diseases | Year: 2013

Treatment of gastric marginal zone B cell lymphoma of MALT (mucosa-associated lymphoid tissue) is nowadays standardized as outlined in the German S3 guideline of 2009 and the European (EGILS) consensus report of 2011. The first choice of treatment is Helicobacter pylori eradication in any case irrespective of H. pylori status and lymphoma stage. Some 70-80% of patients reveal complete remission of MALT lymphoma following successful eradication of the bacterium. Those patients with histologically persisting lymphoma residuals are managed by a watch-and-wait strategy. Nonresponders to H. pylori eradication are referred to radiation with a curative intention in stages I and II. The rare cases of MALT lymphoma of stage III and IV should be treated by chemotherapy. Surgery no longer plays a role in the therapy of gastric MALT lymphoma except for very rare complications such as perforation or bleeding that cannot be controlled endoscopically. Diffuse large B cell lymphoma (DLBCL) is the second most common gastric lymphoma. H. pylori eradication may lead to regression of DLBCL in the individual case. However, immunochemotherapy by a combination of rituximab and the CHOP protocol represents the standard treatment approach in patients with DLBCL and offers a good curative chance. © 2013 S. Karger AG, Basel.


Brandstaetter A.S.,University of Wurzburg | Kleineidam C.J.,University of Konstanz
Journal of Neurophysiology | Year: 2011

In colonies of eusocial Hymenoptera cooperation is organized through social odors, and particularly ants rely on a sophisticated odor communication system. Neuronal information about odors is represented in spatial activity patterns in the primary olfactory neuropile of the insect brain, the antennal lobe (AL), which is analog to the vertebrate olfactory bulb. The olfactory system is characterized by neuroanatomical compartmentalization, yet the functional significance of this organization is unclear. Using two-photon calcium imaging, we investigated the neuronal representation of multicomponent colony odors, which the ants assess to discriminate friends (nestmates) from foes (nonnestmates). In the carpenter ant Camponotus floridanus, colony odors elicited spatial activity patterns distributed across different AL compartments. Activity patterns in response to nestmate and nonnestmate colony odors were overlapping. This was expected since both consist of the same components at differing ratios. Colony odors change over time and the nervous system has to constantly adjust for this (template reformation). Measured activity patterns were variable, and variability was higher in response to repeated nestmate than to repeated nonnestmate colony odor stimulation. Variable activity patterns may indicate neuronal plasticity within the olfactory system, which is necessary for template reformation. Our results indicate that information about colony odors is processed in parallel in different neuroanatomical compartments, using the computational power of the whole AL network. Parallel processing might be advantageous, allowing reliable discrimination of highly complex social odors. © 2011 the American Physiological Society.


Miller I.V.,University of Wurzburg | Grunewald T.G.P.,Institute for Pathology of the LMU Munich
Biology of the Cell | Year: 2015

The discovery of exosomes, which are small, 30-100 nm sized extracellular vesicles that are released by virtual all cells, has initiated a rapidly expanding and vibrant research field. Current investigations are mainly directed toward the role of exosomes in intercellular communication and their potential value as biomarkers for a broad set of diseases. By horizontal transfer of molecular information such as micro RNAs, messenger RNAs or proteins, as well as by receptor-cell interactions, exosomes are capable to mediate the reprogramming of surrounding cells. Herein, we review how especially cancer cells take advantage of this mechanism to influence their microenvironment in favour of immune escape, therapy resistance, tumour growth and metastasis. Moreover, we provide a comprehensive microarray analysis (n > 1970) to study the expression patterns of genes known to be intimately involved in exosome biogenesis across 26 different cancer entities and a normal tissue atlas. Consistent with the elevated production of exosomes observed in cancer patient plasma, we found a significant overexpression especially of RAB27A, CHMP4C and SYTL4 in the corresponding cancer entities as compared to matched normal tissues. Finally, we discuss the immune-modulatory and anti-tumorigenic functions of exosomes as well as innovative approaches to specifically target the exosomal circuits in experimental cancer therapy. © 2015 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.


Winter W.,University of Wurzburg
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We perform an unbiased search of the origin of the recently observed 28 events above ∼30 TeV in the IceCube neutrino observatory, assuming that these are (apart from the atmospheric background) of astrophysical origin produced by photohadronic interactions. Instead of relying on the normalization of the neutrino flux, we demonstrate that spectral shape and flavor composition can be used to constrain or identify the source class. In order to quantify our observations, we use a model where the target photons are produced by the synchrotron emission of coaccelerated electrons, and we include magnetic field effects on the secondary muons, pions, and kaons. We find that the lack of observed events with energies much larger than PeV points towards sources with strong magnetic fields, which do not exhibit a direct correlation between highest cosmic ray and neutrino energies. While the simplest active galactic nuclei models with efficient proton acceleration plausibly describe the current data at about the 3σ confidence level, we show that IceCube can rule out that the observed neutrinos stem from the sources of the ultrahigh-energy cosmic rays with a factor of 10 increased statistics at more than 5σ if the current observations are confirmed. A possible caveat are sources with strong magnetic fields and high Lorentz factors, such as magnetic energy dominated gamma-ray bursts. © 2013 American Physical Society.


Saliba A.-E.,University of Wurzburg | Vonkova I.,Structural and Computational Biology Unit | Gavin A.-C.,Structural and Computational Biology Unit
Nature Reviews Molecular Cell Biology | Year: 2015

Lipids tailor membrane identities and function as molecular hubs in all cellular processes. However, the ways in which lipids modulate protein function and structure are poorly understood and still require systematic investigation. In this Innovation article, we summarize pioneering technologies, including lipid-overlay assays, lipid pull-down assays, affinity-purification lipidomics and the liposome microarray-based assay (LiMA), that will enable protein-lipid interactions to be deciphered on a systems level. We discuss how these technologies can be applied to the charting of system-wide networks and to the development of new pharmaceutical strategies. © 2015 Macmillan Publishers Limited.


Vollmer M.,University of Wurzburg | Vollmer M.,University of California at San Francisco | Beitel R.E.,University of California at San Francisco
Journal of Neurophysiology | Year: 2011

Temporal auditory processing is poor in prelingually hearing-impaired patients fitted with cochlear prostheses as adults. In an animal model of prelingual long-term deafness, we investigated the effects of behavioral training on temporal processing in the adult primary auditory cortex (AI). Neuronal responses to pulse trains of increasing frequencies were recorded in three groups of neonatally deafened cats that received a cochlear prosthesis after >3 yr of deafness: 1) acutely implanted animals that received no electric stimulation before study, 2) animals that received chronic-passive stimulation for several weeks to months before study, and 3) animals that received chronic-passive stimulation and additional behavioral training (signal detection). A fourth group of normal adult cats that was deafened acutely and implanted served as controls. The neuronal temporal response parameters of interest included the stimulus rate that evoked the maximum number of phase-locked spikes [best repetition rate (BRR)], the stimulus rate that produced 50% of the spike count at BRR (cutoff rate), the peak-response latency, and the first spike latency and timing-jitter. All long-deaf animals demonstrated a severe reduction in spiral ganglion cell density (mean, <6% of normal). Long-term deafness resulted in a significantly reduced temporal following capacity and spike-timing precision of cortical neurons in all parameters tested. Neurons in deaf animals that received only chronic-passive stimulation showed a gain in BRR but otherwise were similar to deaf cats that received no stimulation. In contrast, training with behaviorally relevant stimulation significantly enhanced all temporal processing parameters to normal levels with the exception of minimum latencies. These results demonstrate the high efficacy of learning-based remodeling of fundamental timing properties in cortical processing even in the adult, long-deaf auditory system, suggesting rehabilitative strategies for patients with long-term hearing loss. © 2011 the American Physiological Society.


Holzgrabe U.,University of Wurzburg
Chemistry and Biology | Year: 2015

Griselimycin (GM), a natural product isolated a half century ago, is having a bit of a renaissance. After being known for more than 50 years, it is now being pursued as a treatment for tuberculosis. With the new mechanism of action, excellent in vitro and in vivo activity against sensitive and drug-resistant Mycobacterium tuberculosis, and the improved pharmacokinetic properties, the cyclohexyl derivative of GM demonstrates a high translational potential. © 2015 Elsevier Ltd.


Pagliara G.,University of Ferrara | Herzog M.,Max Planck Institute for Astrophysics | Ropke F.K.,University of Wurzburg
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

There are strong indications that the process of conversion of a neutron star into a strange quark star proceeds as a strong deflagration implying that in a few milliseconds almost the whole star is converted. Starting from the three-dimensional hydrodynamic simulations of the combustion process which provide the temperature profiles inside the newly born strange star, we calculate for the first time the neutrino signal that is to be expected if such a conversion process takes place. The neutrino emission is characterized by a luminosity and a duration that is typical for the signal expected from protoneutron stars and represents therefore a powerful source of neutrinos which could be possibly directly detected in case of events occurring close to our Galaxy. We discuss moreover possible connections between the birth of strange stars and explosive phenomena such as supernovae and gamma-ray bursts. © 2013 American Physical Society.


Nakosai S.,University of Tokyo | Budich J.C.,University of Stockholm | Tanaka Y.,Nagoya University | Trauzettel B.,University of Wurzburg | And 2 more authors.
Physical Review Letters | Year: 2013

We study theoretically the proximity effect of a one-dimensional metallic quantum wire (in the absence of spin-orbit interaction) lying on top of an unconventional superconductor. Three different material classes are considered as a substrate: (i) a chiral superconductor in class D with broken time-reversal symmetry and a class DIII superconductor (ii) with and (iii) without a nontrivial Z2 number. Interestingly, we find degenerate zero energy Majorana bound states at both ends of the wire for all three cases. They are unstable against spin-orbit interaction in case (i), while they are topologically protected by time-reversal symmetry in cases (ii) and (iii). Remarkably, we show that nonlocal spin correlations between the two ends of the wire can be simply controlled by a gate potential in our setup. © 2013 American Physical Society.


Winter W.,University of Wurzburg
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We discuss the neutrino mass hierarchy determination with atmospheric neutrinos in Precision IceCube Next Generation Upgrade, based on a simulation with the GLoBES software including the full three flavor framework and parameter degeneracy, and we compare it to long-baseline experiment options. We demonstrate that the atmospheric mass hierarchy sensitivity depends on the achievable experiment properties, and we identify the main targets for optimization, whereas the impact of a large number of tested systematical errors turns out to be small. Depending on the values of θ23, δ, and the true hierarchy, a 90% C.L. to 3σ discovery after three years of operation seems conceivable. We also emphasize the synergy with existing beam and reactor experiments, driven by NOνA, such as the complementary coverage of the parameter space. Finally, we point out that a low intensity neutrino beam with a relatively short decay pipe could be used to determine the mass hierarchy with a sensitivity comparable to the LBNE experiment irrespective of the directional resolution of the detector. © 2013 American Physical Society.


Janotta P.,University of Wurzburg | Lal R.,University of Oxford
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

The framework of generalized probabilistic theories is a popular approach for studying the physical foundations of quantum theory. The standard framework assumes the no-restriction hypothesis, in which the state space of a physical theory determines the set of measurements. However, this assumption is not physically motivated. We generalize the framework to account for systems that do not obey the no-restriction hypothesis. We then show how our framework can be used to describe certain classes of probabilistic theories, for example, those which include intrinsic noise. Relaxing the restriction hypothesis also allows us to introduce a "self-dualization" procedure, which yields a class of theories that share many features of quantum theory. We then characterize joint states, generalizing the maximal tensor product. We show how this tensor product can be used to describe the convex closure of the Spekkens toy theory, and in doing so we obtain an analysis of why it is local in terms of the geometry of its state space. We show that the unrestricted version of the Spekkens toy theory is the theory known as "boxworld" that allows maximal nonlocal correlations. © 2013 American Physical Society.


The electron microprobe (EMP) Th-U-Pb monazite bulk chemical dating method was applied to granulite-facies rocks of the Wilson Terrane in Antarctica. A combination of this method to isotopic U-Pb-SHRIMP ages for the evaluation of metamorphic processes required the analysis of reference monazites. These can be subdivided into three groups: a) Monazite with variable total Pb at constant Th (e.g. VK-1) is unsuitable for EMP data evaluation; b) Monazite with highly variable total Pb and Th, but with at least some Th/Pb approximating an apparent isochrone (e.g. MPN) is partly useful; and c) Monazite with constant Th/Pb at high Th (e.g. Madmon monazite) is best suitable for the combined approach and can be additionally used to improve the Th calibration for EMP. Study of monazite in grain mounts and in thin sections led to partly different but complementary results: Older monazites with EMP ages up to 680. Ma occur mainly in a grain mount from diatexite and metatexite and are interpreted as detrital relics. Some of these monazites show structures and mineral-chemical zonation trends resembling metasomatism by alkali-bearing fluids. A marked mobility of Th, P, Ce, Si and U is observed. The age of the metasomatic event can be bracketed between 510 and 450. Ma. Furthermore, in the grain mount and in numerous petrographic thin sections of migmatites and gneisses, the EMP Th-U-Pb and SHRIMP U-Pb monazite data uniformly signal a major metamorphic event with a medium-pressure granulite facies peak between 512 and 496. Ma. Subsequent isothermal uplift and then amphibolite-facies conditions between 488 and 466. Ma led to crystallisation of pristine monazite. The high-grade metamorphic event, related to the Ross Orogeny, can be uniformly traced more than 600. km along strike in the Wilson Terrane. © 2013 Elsevier B.V.


Dashkovskiy S.,University of Bremen | Kosmykov M.,University of Bremen | Wirth F.R.,University of Wurzburg
IEEE Transactions on Automatic Control | Year: 2011

We consider interconnected nonlinear systems with external inputs, where each of the subsystems is assumed to be input-to-state stable (ISS). Sufficient conditions of small-gain type are provided guaranteeing that the interconnection is ISS with respect to the external input. To this end we extend recently obtained small-gain theorems to a more general type of interconnections. The small-gain theorem provided here is applicable to situations where the ISS conditions are formulated differently for each subsystem and are either given in the maximization or the summation sense. Furthermore, it is shown that the conditions are compatible in the sense that it is always possible to transform sum formulations to maximum formulations without destroying a given small-gain condition. An example shows the advantages of our results in comparison with the known ones. © 2006 IEEE.


Sturm C.,University of Wurzburg
Nuclear Physics B | Year: 2013

The running of the effective electromagnetic coupling is for many electroweak observables the dominant correction. It plays an important role for deriving constraints on the Standard Model in the context of electroweak precision measurements. We compute the four-loop QED corrections to the running of the effective electromagnetic coupling and perform a numerical evaluation of the different gauge invariant subsets. © 2013 Elsevier B.V.


Glock C.H.,University of Wurzburg
Computers and Industrial Engineering | Year: 2011

Supply chain management is concerned with the coordination of material and information flows in multi-stage production systems. A closer look at the literature reveals that previous research on the coordination of multi-stage production systems has predominantly focused on the sales side of the supply chain, whereas problems that arise on the supply side have often been neglected. This article closes this gap by studying the coordination of a supplier network in an integrated inventory model. Specifically, we consider a buyer sourcing a product from heterogeneous suppliers and tackle both the supplier selection and lot size decision with the objective to minimise total system costs. First, we provide mathematical formulations for the problem under study, and then suggest a two-stage solution procedure to derive a solution. Numerical studies indicate that our solution procedure reduces the total number of supplier combinations that have to be tested for optimality, and that it may support initiatives which aim on increasing the efficiency of the supply chain as a heuristic planning tool. © 2010 Elsevier Ltd. All rights reserved.


Tonelli M.A.,University of Alberta | Wanner C.,University of Wurzburg
Kidney International Supplements | Year: 2013

The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease (CKD) provides guidance on lipid management and treatment for all patients with CKD (non-dialysis-dependent, dialysis-dependent, kidney transplant recipients and children). This guideline contains chapters on the assessment of lipid status and treatment for dyslipidemia in adults and children. Development of the guideline followed an explicit process of evidence review and appraisal. Treatment approaches are addressed in each chapter and guideline recommendations are based on systematic reviews of relevant trials. Appraisal of the quality of the evidence and the strength of recommendations followed the GRADE approach. Ongoing areas of controversies and limitations of the evidence are discussed and additional suggestions are also provided for future research. © 2013 KDIGO.


Tessmer I.,University of Wurzburg | Fried M.G.,University of Kentucky
DNA Repair | Year: 2014

The O6-alkylguanine DNA alkyltransferase (AGT) is a highly conserved protein responsible for direct repair of alkylated guanine and to a lesser degree thymine bases. While specific DNA lesion-bound complexes in crystal structures consist of monomeric AGT, several solution studies have suggested that cooperative DNA binding plays a role in the physiological activities of AGT. Cooperative AGT-DNA complexes have been described by theoretical models, which can be tested by atomic force microscopy (AFM). Direct access to structural features of AGT-DNA complexes at the single molecule level by AFM imaging revealed non-specifically bound, cooperative complexes with limited cluster length. Implications of cooperative binding in AGT-DNA interactions are discussed. © 2014 Elsevier B.V.


Kuhn M.,University of Wurzburg
Physiological reviews | Year: 2016

cGMP controls many cellular functions ranging from growth, viability, and differentiation to contractility, secretion, and ion transport. The mammalian genome encodes seven transmembrane guanylyl cyclases (GCs), GC-A to GC-G, which mainly modulate submembrane cGMP microdomains. These GCs share a unique topology comprising an extracellular domain, a short transmembrane region, and an intracellular COOH-terminal catalytic (cGMP synthesizing) region. GC-A mediates the endocrine effects of atrial and B-type natriuretic peptides regulating arterial blood pressure/volume and energy balance. GC-B is activated by C-type natriuretic peptide, stimulating endochondral ossification in autocrine way. GC-C mediates the paracrine effects of guanylins on intestinal ion transport and epithelial turnover. GC-E and GC-F are expressed in photoreceptor cells of the retina, and their activation by intracellular Ca(2+)-regulated proteins is essential for vision. Finally, in the rodent system two olfactorial GCs, GC-D and GC-G, are activated by low concentrations of CO2and by peptidergic (guanylins) and nonpeptidergic odorants as well as by coolness, which has implications for social behaviors. In the past years advances in human and mouse genetics as well as the development of sensitive biosensors monitoring the spatiotemporal dynamics of cGMP in living cells have provided novel relevant information about this receptor family. This increased our understanding of the mechanisms of signal transduction, regulation, and (dys)function of the membrane GCs, clarified their relevance for genetic and acquired diseases and, importantly, has revealed novel targets for therapies. The present review aims to illustrate these different features of membrane GCs and the main open questions in this field. Copyright © 2016 the American Physiological Society.


We compute the decoupling function of the MS renormalized fine-structure constant up to four-loop order in perturbative QCD. The results are used in order to determine the related top-quark contributions to the Higgs-boson decay into two photons in the heavy top-quark mass limit to order α4 s. © 2014, The Author(s).


Stoggl T.,University of Salzburg | Stoggl T.,Mid Sweden University | Sperlich B.,University of Wurzburg
Frontiers in Physiology | Year: 2014

Endurance athletes integrate four conditioning concepts in their training programs: high-volume training (HVT), "threshold-training" (THR), high-intensity interval training (HIIT) and a combination of these aforementioned concepts known as polarized training (POL). The purpose of this study was to explore which of these four training concepts provides the greatest response on key components of endurance performance in well-trained endurance athletes. Methods: Forty eight runners, cyclists, triathletes, and cross-country skiers (peak oxygen uptake: (VO2peak): 62.6 ± 7.1 mL·min-1·kg-1) were randomly assigned to one of four groups performing over 9 weeks. An incremental test, work economy and a VO2peak tests were performed. Training intensity was heart rate controlled. Results: POL demonstrated the greatest increase in VO2peak (+6.8 ml·min·kg-1 or 11.7%, P < 0.001), time to exhaustion during the ramp protocol (+17.4%, P < 0.001) and peak velocity/power (+5.1%, P < 0.01). Velocity/power at 4 mmol·L-1 increased after POL (+8.1%, P < 0.01) and HIIT (+5.6%, P < 0.05). No differences in pre- to post-changes of work economy were found between the groups. Body mass was reduced by 3.7% (P < 0.001) following HIIT, with no changes in the other groups. With the exception of slight improvements in work economy in THR, both HVT and THR had no further effects on measured variables of endurance performance (P > 0.05). Conclusion: POL resulted in the greatest improvements in most key variables of endurance performance in well-trained endurance athletes. THR or HVT did not lead to further improvements in performance related variables. © 2014 Stöggl and Sperlich.


Schmitt A.G.,University of Wurzburg
Current topics in medicinal chemistry | Year: 2016

Alzheimer's disease (AD) is the most prevalent human neurodegenerative disease. Disturbances of brain glucose uptake, glucose tolerance, glucose utilization and of the insulin/insulin receptor signaling cascade are thought to be key features of the pathophysiology of AD. Changes in energy homeostasis in the brain and in the periphery dramatically influence the proliferation of adult neural stem cells and neurogenesis in the hippocampus. Recent findings suggest that adult neurogenesis is altered in the hippocampus of AD patients and in various animal models of AD. Several factors associated with the pathogenesis of AD are also known to be involved in the regulation of adult neurogenesis. Understanding the mechanisms underlying these changes at different stages of AD could provide insights into its pathogenesis, contribute to identifying biomarkers of early AD, and supply fundamental knowledge that will allow novel therapeutic approaches to treating AD by intervening in adult neurogenesis. In this review we provide an overview of the connections between energy metabolism, adult neurogenesis and AD.


Koepsell H.,University of Wurzburg
Current Opinion in Nephrology and Hypertension | Year: 2013

PURPOSE OF REVIEW: Secretion and reabsorption of organic cations in kidney is mediated by polyspecific transporters with broadly overlapping substrate specificity. Knowledge concerning function, transported compounds, clinical impact of mutations in the transporters and drug-drug interactions is rapidly increasing. Recent research concerning properties of these transporters and their clinical significance for nephrology is summarized. RECENT FINDINGS: Recent data showed that the organic cation transporters OCT1-3 form homo-oligomers, and that oligomerization is important for transporter targeting to the plasma membrane. A functional relevant substrate binding hinge domain in these transporters has been identified. Screening of 900 prescription drugs for interaction with the H-organic cation transporter hMATE1 indicated that 10% of the drugs are inhibitors and that 0.5% are effective under clinical conditions. The pivotal role of hOCT2 for renal secretion of creatinine and metformin was confirmed in clinical studies. SUMMARY: Organic cation transporters of the transporter families SLC22 and SLC47 are critically involved in the renal secretion of various cationic drugs. Drug-drug interactions at the transporter level and mutations in the transporters lead to changes in pharmacokinetics and influence nephrotoxicity of drugs. Further studies are required to improve drug therapies.


Lampert K.P.,Ruhr University Bochum | Schartl M.,University of Wurzburg
BMC Biology | Year: 2010

A re-examination of the mitochondrial genomes of unisexual salamander lineages, published in BMC Evolutionary Biology, shows them to be the oldest unisexual vertebrates known, having been around for 5 million years. This presents a challenge to the prediction that lack of genetic recombination is a fast track to extinction.© 2010 Lampert and Schartl; licensee BioMed Central Ltd.


Bornscheuer U.,University of Greifswald | Buchholz K.,Institute For Technische Chemie | Seibel J.,University of Wurzburg
Angewandte Chemie - International Edition | Year: 2014

Glycoside-degrading enzymes play a dominant role in the biochemical conversion of cellulosic biomass into low-price biofuels and high-value-added chemicals. New insight into protein functions and substrate structures, the kinetics of recognition, and degradation events has resulted in a substantial improvement of our understanding of cellulose degradation. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Malet-Martino M.,French National Center for Scientific Research | Holzgrabe U.,University of Wurzburg
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

This article focuses on the description of some of the NMR techniques used in the field of biomedical and pharmaceutical research. Indeed, the NMR method has special characteristics which make it uniquely suitable for these kinds of studies. It is non-selective so that all the low molecular weight compounds in the sample investigated are detected simultaneously in a single run. NMR also provides rich structural information which is an important asset to characterize complex mixture components. NMR is quantitative, i.e. the area of a NMR signal is directly proportional to the number of corresponding nuclei and thus, at variance with other techniques, the response factor is not dependent on the molecular structure. It is also a non-invasive tool that permits in vivo studies in humans. Compared with other techniques, NMR is significantly insensitive, which represents the main drawback of the technique. The recent technological developments of the technique have nevertheless considerably improved its sensitivity. The first part of this article presents an overview of the advantages and limitations of NMR for in vitro quantitative analysis of complex matrices in liquid or semi-solid phases. The second part deals with the NMR-based metabolomics methodology. The third part describes the in vivo clinical magnetic resonance spectroscopy techniques. The fourth part reports some examples of NMR applications in the biomedical and pharmaceutical research fields. © 2010 Elsevier B.V.


Kadler M.,University of Wurzburg
Nature Physics | Year: 2016

The astrophysical sources of the extraterrestrial, very high-energy neutrinos detected by the IceCube collaboration remain to be identified. Gamma-ray (γ-ray) blazars have been predicted to yield a cumulative neutrino signal exceeding the atmospheric background above energies of 100 TeV, assuming that both the neutrinos and the γ-ray photons are produced by accelerated protons in relativistic jets. As the background spectrum falls steeply with increasing energy, the individual events with the clearest signature of being of extraterrestrial origin are those at petaelectronvolt energies. Inside the large positional-uncertainty fields of the first two petaelectronvolt neutrinos detected by IceCube, the integrated emission of the blazar population has a sufficiently high electromagnetic flux to explain the detected IceCube events, but fluences of individual objects are too low to make an unambiguous source association. Here, we report that a major outburst of the blazar PKS B1424–418 occurred in temporal and positional coincidence with a third petaelectronvolt-energy neutrino event (HESE-35) detected by IceCube. On the basis of an analysis of the full sample of γ-ray blazars in the HESE-35 field, we show that the long-term average γ-ray emission of blazars as a class is in agreement with both the measured all-sky flux of petaelectronvolt neutrinos and the spectral slope of the IceCube signal. The outburst of PKS B1424–418 provides an energy output high enough to explain the observed petaelectronvolt event, suggestive of a direct physical association. © 2016 Nature Publishing Group


Unger M.,University of Wurzburg
Drug Metabolism Reviews | Year: 2013

Ginkgo biloba leaf extracts (GLEs) are popular herbal remedies for the treatment of Alzheimer's dementia, tinnitus, vertigo and peripheral arterial disease. As GLEs are taken regularly by older people who are likely to also use multiple other drugs for the treatment of, e.g. hypertension, diabetes, rheumatism or heart failure, potential herb-drug interactions are of interest. Preclinical studies of high doses/concentrations of GLEs of varying quality and standardization hinted at both an inhibition and induction of metabolic enzymes and transporters. However, in humans, positive in vitro-findings could not be replicated in vivo. At maximum recommended doses of 240mg/day, a clinically relevant interaction potential of the standardized GLE EGb 761 could not be shown. GLE doses higher than the recommended ones led to a weak induction of the CYP2C19-mediated omeprazole 5-hydroxylation, and a weak inhibition of the CYP3A4-mediated midazolam 1′-hydroxylation, respectively. Also, the regular intake of a poorly characterized GLE at a dose of 360mg/day slightly increased the bioavailability of talinolol, a substrate of P-glycoprotein and various organic anion-transporting polypeptides. Thus, regarding pharmacokinetic herb-drug interactions, the intake of the standardized GLE, EGb 761, together with synthetic drugs appears to be safe as long as daily doses up to 240mg are consumed. If this applies to other extracts prepared according to the European Pharmacopoeia remains uncertain. Also, a relevant potential for drug interactions cannot be excluded for poorly standardized GLEs used in many food supplements. © 2013 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.


Besides the uniaxial nematic phase, omnipresent in liquid crystal (LC) displays, the biaxial nematic phase has been theoretically proposed to exist in which all molecular axes are oriented along individual directors. Although some high molecular mass systems (lyotropic phases, LC-polymers and colloidal LCs) reveal this fascinating phase, the formation of the thermotropic biaxial nematic phase among low molecular mass systems is strongly debated. This article gives a brief review of the methods frequently used to detect biaxiality and the different molecular biaxial systems which are under consideration to assemble in such a biaxial nematic phase. It appears that molecular design is in a vicious circle with respect to the preparation of ideal mesogens which should possess an enantiotropic, true biaxial nematic phase of molecules at ambient temperature and with a sufficiently low viscosity for a possible application in fast switching biaxial LC displays. © 2011 Taylor & Francis.


Kollist H.,University of Tartu | Nuhkat M.,University of Tartu | Roelfsema M.R.G.,University of Wurzburg
New Phytologist | Year: 2014

Contents: 44 I. 44 II. 45 III. 46 IV. 53 V. 56 57 References 57 Summary: Stomata are an attractive experimental system in plant biology, because the responses of guard cells to environmental signals can be directly linked to changes in the aperture of stomatal pores. In this review, the mechanics of stomatal movement are discussed in relation to ion transport in guard cells. Emphasis is placed on the ion pumps, transporters, and channels in the plasma membrane, as well as in the vacuolar membrane. The biophysical properties of transport proteins for H+, K+, Ca2+, and anions are discussed and related to their function in guard cells during stomatal movements. Guard cell signaling pathways for ABA, CO2, ozone, microbe-associated molecular patterns (MAMPs) and blue light are presented. Special attention is given to the regulation of the slow anion channel (SLAC) and SLAC homolog (SLAH)-type anion channels by the ABA signalosome. Over the last decade, several knowledge gaps in the regulation of ion transport in guard cells have been closed. The current state of knowledge is an excellent starting point for tackling important open questions concerning stress tolerance in plants. © 2014 New Phytologist Trust.


Bramkamp M.,Ludwig Maximilians University of Munich | Lopez D.,University of Wurzburg
Microbiology and Molecular Biology Reviews | Year: 2015

An interesting concept in the organization of cellular membranes is the proposed existence of lipid rafts. Membranes of eukaryotic cells organize signal transduction proteins into membrane rafts or lipid rafts that are enriched in particular lipids such as cholesterol and are important for the correct functionality of diverse cellular processes. The assembly of lipid rafts in eukaryotes has been considered a fundamental step during the evolution of cellular complexity, suggesting that bacteria and archaea were organisms too simple to require such a sophisticated organization of their cellular membranes. However, it was recently discovered that bacteria organize many signal transduction, protein secretion, and transport processes in functional membrane microdomains, which are equivalent to the lipid rafts of eukaryotic cells. This review contains the most significant advances during the last 4 years in understanding the structural and biological role of lipid rafts in bacteria. Furthermore, this review shows a detailed description of a number of molecular and genetic approaches related to the discovery of bacterial lipid rafts as well as an overview of the group of tentative lipid-protein and protein-protein interactions that give consistency to these sophisticated signaling platforms. Additional data suggesting that lipid rafts are widely distributed in bacteria are presented in this review. Therefore, we discuss the available techniques and optimized protocols for the purification and analysis of raft-associated proteins in various bacterial species to aid in the study of bacterial lipid rafts in other laboratories that could be interested in this topic. Overall, the discovery of lipid rafts in bacteria reveals a new level of sophistication in signal transduction and membrane organization that was unexpected for bacteria and shows that bacteria are more complex than previously appreciated. Copyright © 2015, American Society for Microbiology. All Rights Reserved.


Reiners C.,University of Wurzburg
Journal of endocrinological investigation | Year: 2012

Recombinant human TSH (rhTSH) (thyrotropin alfa, Genzyme Co.) has been developed to improve the management of patients with differentiated thyroid cancer, who need radioiodine (131I) for treatment or follow-up diagnosis. Data available from published series involving approximately 500 patients prove that rhTSH is safe and that mostly unspecific non-severe side effects may occur (e.g. nausea, vomiting, headache or fatigue and dizziness). Tumor swelling which has been occasionally observed after rhTSH injection is a phenomenon well known from the past attributed to endogenous TSH stimulation after thyroid hormone withdrawal (THW) and can be prevented or alleviated by concomitant administration of glucocorticoids. The absorbed dose to the tumor after preparation of 131I therapy with rhTSH as compared to THW is not statistically different. The radiation dose to the blood and the remainder, however, is significantly lower if rhTSH is used instead of THW which is a strong argument in favor of rhTSH. Most importantly, the quality of life (QOL) after rhTSH is preserved as compared to THW where symptoms of hypothyroidism significantly impair QOL. Last but not least, more convenient scheduling of patients and shorter duration of time to be spent in the radioprotective ward are further arguments in favor of rhTSH.


Jahn D.,University of Wurzburg
Nucleus (Austin, Tex.) | Year: 2012

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.


Conservation of light energy in photosynthesis is possible only in hydrated photoautotrophs. It requires complex biochemistry and is limited in capacity. Charge separation in reaction centres of photosystem II initiates energy conservation but opens also the path to photooxidative damage. A main mechanism of photoprotection active in hydrated photoautotrophs is controlled by light. This is achieved by coupling light flux to the protonation of a special thylakoid protein which activates thermal energy dissipation. This mechanism facilitates the simultaneous occurrence of energy conservation and energy dissipation but cannot completely prevent damage by light. Continuous metabolic repair is required to compensate damage. More efficient photoprotection is needed by desiccation-tolerant photoautotrophs. Loss of water during desiccation activates ultra-fast energy dissipation in mosses and lichens. Desiccation-induced energy dissipation neither requires a protonation reaction nor light but photoprotection often increases when light is present during desiccation. Two different mechanisms contribute to photoprotection of desiccated photoautotrophs. One facilitates energy dissipation in the antenna of photosystem II which is faster than energy capture by functional reaction centres. When this is insufficient for full photoprotection, the other one permits energy dissipation in the reaction centres themselves. © 2012 Springer Science+Business Media B.V.


Barkeshli M.,Microsoft | Jiang H.-C.,University of California at Berkeley | Jiang H.-C.,SLAC | Thomale R.,University of Wurzburg | Qi X.-L.,Stanford University
Physical Review Letters | Year: 2015

We present a wide class of partially integrable lattice models with two-spin interactions which generalize the Kitaev honeycomb model. These models have a conserved quantity associated with each plaquette, conserved large loop operators on the torus, and topological degeneracy. We introduce a "slave-genon" approach which generalizes the Majorana fermion approach in the Kitaev model. The Hilbert space of our spin model can be embedded in an enlarged Hilbert space of non-Abelian twist defects, referred to as genons. In the enlarged Hilbert space, the spin model is exactly reformulated as a model of non-Abelian genons coupled to a discrete gauge field. We discuss in detail a particular Z3 generalization, and we show that in a certain limit the model is analytically tractable and produces a non-Abelian topological phase with chiral parafermion edge states. © 2015 American Physical Society.


Dent S.,University of Ottawa | Oyan B.,Yeditepe University | Honig A.,University of Wurzburg | Mano M.,University of Sao Paulo | Howell S.,University of Manchester
Cancer Treatment Reviews | Year: 2013

Targeting human epidermal growth factor receptor 2 (HER2) during or in sequence with chemotherapy improves overall survival in metastatic and early HER2-overexpressing breast cancer. In this paper we systematically review neoadjuvant clinical trial data in HER2-positive breast cancer and discuss key unanswered clinical questions.All trials of HER2-targeted neoadjuvant therapy were identified through non-date-limited searches of PubMED® and Biosis® and congress abstract book searches from 2000-2011. Eligible trials were prospective, had at least 10 patients and a clear definition of pathological complete response (pCR) rate.A total of 50 trials fulfilled the eligibility criteria; 41 single-arm phase II studies were identified, 37 with trastuzumab and 4 with lapatinib, with significant variability in baseline tumour characteristics and pCR rates (range 12-66.7%). Of 9 randomised phase II/III trials, 4 assessed the addition of trastuzumab to chemotherapy and a further 5 randomised trials assessed different HER2-targeting approaches. Four of these studies assessed dual HER2-targeting approaches, which universally increased pCR at the expense of increased non-cardiac toxicity when lapatinib, but not pertuzumab, was added to trastuzumab.Significant advances have been made in HER2 targeting, resulting in a marked increase in the number of breast cancer patients experiencing tumour pCR. Mature data from randomised neoadjuvant and adjuvant studies are awaited for survival outcomes with combination targeted approaches. Unanswered questions centre on the individualisation of therapy and include; which, if any, chemotherapy backbone should be used, and which patients need dual HER2 blockade? © 2013 .


Stolz A.,University of Stuttgart | Hilt W.,University of Stuttgart | Buchberger A.,University of Wurzburg | Wolf D.H.,University of Stuttgart
Trends in Biochemical Sciences | Year: 2011

Cdc48 is an essential, highly prominent ATP driven machine in eukaryotic cells. Physiological function of Cdc48 has been found in a multitude of cellular processes, for instance cell cycle progression, homotypic membrane fusion, chromatin remodeling, transcriptional and metabolic regulation, and many others. The molecular function of Cdc48 is arguably best understood in endoplasmic reticulum-associated protein degradation by the ubiquitin proteasome system. In this review, we summarize the general characteristics of Cdc48/p97 and the most recent results on the molecular function of Cdc48 in some of the above processes, which were found to finally end in proteolysis-connected pathways, either involving the proteasome or autophagocytosis-mediated lysosomal degradation. © 2011 Elsevier Ltd.


Kissler S.,University of Wurzburg
Trends in Molecular Medicine | Year: 2011

Autoimmunity cannot yet be prevented or cured, in large part due to our poor understanding of disease etiology. Remarkable advances in genomic technology have recently enabled the discovery of a large number of disease-associated gene variations by genome-wide association studies. The next step towards understanding autoimmune disorders entails the functional study of susceptibility genes within experimental disease models. RNA interference (RNAi) is a promising tool for such investigations. Several features of RNAi, including its specificity, versatility and reversible nature, allow experimental systems to be tailored to relevant gene variations. This review discusses how the experimental use of RNAi is invaluable in bridging the gap between the identification of susceptibility genes and the elucidation of their functional contribution to autoimmune disease. © 2011 Elsevier Ltd.


Rey G.D.,University of Wurzburg
Computers in Human Behavior | Year: 2010

The experiment investigated whether layout of cause and effect affects learning for causal connections in a simple computer simulation. Students (N = 113) used an introductory text and a simulation to learn central concepts about neural networks and then took a retention and transfer test. Each learner was randomly assigned to one cell of a 2 (compliance with reading direction or not) × 2 (with or without signaling) between subjects factorial design. Students who obtained the causal connection in reading direction (the cause is positioned on the left side, the effect is placed on the right side) performed better on transfer than did students, for whom the reading direction was reversed (from right to left). Furthermore, signals that indicated the layout of the causal connection fostered transfer performance and reduced time spent with the simulation. These results are consistent with the signaling principle and the cognitive theory of multimedia learning. © 2010 Elsevier Ltd. All rights reserved.


Holzschuh A.,University of Wurzburg | Holzschuh A.,University of Gottingen | Dudenhoffer J.-H.,University of Gottingen | Tscharntke T.,University of Gottingen
Biological Conservation | Year: 2012

More than 70% of the leading global food crops, accounting for 35% of the global food production, are affected by pollination of flower-visiting animals, but the main pollinators - managed honey bees and wild bees - are currently declining in many regions worldwide. For the vast majority of crops it is unknown whether managed honey bees or wild bees are the most efficient pollinators, and how the pollination service provided by wild bees can be ensured. We assessed in a landscape-scale study how sweet cherry production is influenced (1) by high-diversity bee habitats, and (2) by flowering ground vegetation which might compete with cherry for pollinators or might facilitate cherry pollination. Cherry was highly dependent on insect pollination with bagged flowers producing only 3% of the fruits produced by open-pollinated flowers. Although two thirds of all flower visitors were honey bees, fruit set was related to wild bee visitation only, presumably due to their higher pollination efficiency. Initial fruit set and final cherry yield were closely correlated. Wild bee visitation increased with the proportion of high-diversity bee habitats in the surrounding landscape (1. km radius). An increase of high-diversity bee habitats in the landscape from 20% to 50% enhanced fruit set by 150%, which was experimentally shown to be due to pollen limitation. Neither flower cover of ground vegetation nor bee densities on ground transects were related to flower visitation in trees or fruit set. Our results show that pollination services by wild bees in cherry surpassed pollination by honey bees. Hence, farmers need to protect semi-natural habitats in their landscapes to guarantee pollination and high yields. The conservation of semi-natural habitats, which provide nesting sites and additional food resources before and after cherry flowering enhances gratis ecosystem services, and thereby, the farmer's yield. © 2012 Elsevier Ltd.


Staub F.,University of Wurzburg
Computer Physics Communications | Year: 2010

SARAH is a Mathematica package for building and studying supersymmetric models. It calculates for a given superpotential and gauge sector the full Lagrangian of a model. With the new version of SARAH it is possible to calculate automatically all interactions for the different eigenstates and write model files for FeynArts and CompHep/CalcHep. In addition, the tadpole equations are calculated, gauge fixing terms can be given and ghost interactions are added, particles can be integrated out and non-supersymmetric limits of the theory can be chosen. CP and flavor violation can easily be switched on or off. © 2010 Elsevier B.V. All rights reserved.


Lutz M.B.,University of Wurzburg | Inaba K.,Kyoto University | Schuler G.,Friedrich - Alexander - University, Erlangen - Nuremberg | Romani N.,Innsbruck Medical University
Immunity | Year: 2016

In a recent article (Helft et al., 2015), murine bone marrow (BM) cultures with granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed for macrophage ("GM-Mac") and dendritic cell ("GM-DC") subsets, and the GM-DC subset was compared with conventional or classical DC (cDC) subsets isolated from peripheral and lymphoid organs of mice. The article was accompanied by a preview about the usefulness of murine BM-DC cultures in the study of DC biology (Guilliams and Malissen, 2015), insinuating that BM-DCs are not real DCs. But what is a real DC? To reanimate the "DC-ness" of murine BM-DCs, we collected some additional points that have not been addressed by recent papers or comments. We suggest their consideration for further discussion. In a recent article (Helft et al., 2015), murine bone marrow (BM) cultures with granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed for macrophage ("GM-Mac") and dendritic cell ("GM-DC") subsets, and the GM-DC subset was compared with conventional or classical DC (cDC) subsets isolated from peripheral and lymphoid organs of mice. The article was accompanied by a preview about the usefulness of murine BM-DC cultures in the study of DC biology (Guilliams and Malissen, 2015), insinuating that BM-DCs are not real DCs. But what is a real DC? To reanimate the "DC-ness" of murine BM-DCs, we collected some additional points that have not been addressed by recent papers or comments. We suggest their consideration for further discussion. © 2016 Elsevier Inc.


Meloni D.,University of Wurzburg
Journal of Physics G: Nuclear and Particle Physics | Year: 2010

We present a supersymmetric see-saw S4 model giving rise to the most general neutrino mass matrix compatible with tri-bimaximal mixing. We adopt the S4 × Z5 flavour symmetry, broken by suitable vacuum expectation values of a small number of flavon fields. We show that the vacuum alignment is a natural solution of the most general superpotential allowed by the flavour symmetry, without introducing any soft breaking terms. In the charged lepton sector, mass hierarchies are controlled by the spontaneous breaking of the flavour symmetry caused by the vevs of one doublet and one triplet flavon fields instead of using the Froggatt-Nielsen U(1) mechanism. The next to leading order corrections to both charged lepton mass matrix and flavon vevs generate corrections to the mixing angles as large as O(λ C 2). Applied to the quark sector, the symmetry group S4 × Z5 can give a leading order VCKM proportional to the identity as well as a matrix with coefficients in the Cabibbo 2 × 2 submatrix. Higher order corrections produce nonvanishing entries in the other VCKM entries which are generically of O(λC 2). © 2010 IOP Publishing Ltd.


Scheer U.,University of Wurzburg
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

Boveri's visionary monograph 'Ueber die Natur der Centrosomen' (On the nature of centrosomes) in 1900 was founded primarily on microscopic observations of cleaving eggs of sea urchins and the roundworm parasiteAscaris. As Boveri wrote in the introductory paragraph, his interests were less about morphological aspects of centrosomes, but rather aimed at an understanding of their physiological role during cell division. The remarkable transition from observations of tiny dot-like structures in fixed and sectioned material to a unified theory of centrosome function (which in essence still holds true today) cannot be fully appreciated without examining Boveri's starting material, the histological specimens. It was generally assumed that the microscope slides were lost during the bombing of the Zoological Institute in Würzburg at the end of WWII. Here, I describe the discovery of a number of Boveri's original microscope slides with serial sections of early sea urchin andAscarisembryos, stained by Heidenhain's iron haematoxylin method. Some slides bear handwritten notes and sketches by Boveri. Evidence is presented that the newly discovered slides are part of the original material used by Boveri for his seminal centrosome monograph. © 2014 The Author(s) Published by the Royal Society.


Kirsch W.,University of Wurzburg | Hennighausen E.,University of Marburg
Clinical Neurophysiology | Year: 2010

Objective: This study examined the sensitivity of event-related cortical potentials (ERPs) preceding and accompanying goal-directed hand movements to the variation of movement distance. Methods: Participants performed linear hand movements to memorized target locations, which were arranged in distances between 10 and 31. cm from the starting position of the hand. EPRs were analyzed time-locked to the imperative go signal as well as to the movement onset. Results: An increase in target distance was associated with an increase in amplitude of a negative component measured over sensorimotor areas that preceded movement onset (MP). Another negative deflection arising at similar scalp locations (N4) and following the MP decline was also highly distance dependent. Conclusions: The data demonstrate distance specific brain activity accompanying accelerative and decelerative phases of motion during goal-directed hand movements. Significance: The modulation of MP may to be related to the modulation of the initial force pulse, while N4 effects may reflect distance dependent changes in the magnitude of decelerative control. © 2010 International Federation of Clinical Neurophysiology.


Magnus T.,University of Hamburg | Wiendl H.,University of Munster | Kleinschnitz C.,University of Wurzburg
Current Opinion in Neurology | Year: 2012

Purpose of Review: Only recently has it been realized that immune mechanisms contribute to the pathophysiology of ischemic stroke, which for many years was regarded mainly as a vascular disease. These immunologic processes are present during all stages of stroke and involve both the innate and adaptive immune systems. This review highlights the latest findings related to the 'immunology of stroke'. Recent Findings: During the early phase of an ischemic insult, 'danger signals' such as ATP are released from dying tissue to subsequently attract inflammatory cells. Unexpectedly, T cells have been identified as prominent mediators of stroke-induced tissue damage. Whereas during the acute stage of infarction T cells act independently from antigen-specific stimuli but rather interact with thrombotic pathways, antigen-dependent T-cell activation might be relevant at later stages. Moreover, certain T-cell subsets like γδ T cells or regulatory T cells are able to influence stroke outcome either in a detrimental or beneficial way. Finally, proof-of-principle studies using FTY720 or VLA-4 blockers have demonstrated that the concept of 'immunomodulation in stroke' is feasible. Summary: The insight that ischemic stroke at least in part is an immune-mediated disease may open new avenues for the treatment of this devastating neurologic condition. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Speer C.P.,University of Wurzburg
Neonatology | Year: 2011

Surfactant substitution has been a major breakthrough in the treatment of neonatal respiratory distress syndrome (RDS), primarily caused by a lack of pulmonary surfactant; it has significantly reduced mortality and acute pulmonary morbidity in preterm infants. Some very immature infants, however, have a poor response to surfactant replacement or an early relapse. This brief article is based on the hypothesis that neonatal RDS has a complex and multifactorial pathogenesis characterized by an injurious inflammatory sequence in the immature lung. Fetal exposure to chorioamnionitis has been shown to initiate an inflammatory reaction beginning in utero. A 'low-grade' inflammatory stimulus in utero may 'prime' the fetal lung for accelerated maturation of the surfactant system, especially in conjunction with prenatal steroids, and may protect the preterm infant from developing moderate to severe RDS. Depending on the severity of inflammatory injury to the alveolar-capillary unit, however, serum proteins will leak into the airways and induce surfactant inactivation. Following this intrauterine 'first hit', the immature infant may develop severe RDS and have a poor response to surfactant substitution. Secondary insults such as traumatic stabilization techniques, oxygen toxicity, initiation of mechanical ventilation and others injure the immature lung immediately after birth and perpetuate and may aggravate the inflammatory process. Observational studies in preterm infants and animal experiments support this concept. Whenever surfactant inactivation is suspected, higher or repetitive doses of natural surfactant may help to overcome surfactant inactivation and to restore lung function. Copyright © 2011 S. Karger AG, Basel.


Carbon monoxide is now well-established as a small-molecule biological effector in the human body. Metal-carbonyl complexes are a promising way to achieve safe and controlled delivery of CO for therapeutic applications and thus, such CO releasing molecules (CORMs) have achieved significant attention in the last 10 years. In most CORMs, the liberation of carbon monoxide is triggered by hydrolytic processes in aqueous medium and thus their half-life under physiological conditions determines their potential therapeutic utility. To overcome such limitations, photo-induced CO release from dark-stable metal-carbonyl complex prodrugs is an interesting alternative. Thus, in this review, the current knowledge on PhotoCORMs is summarized and their properties critically evaluated. The main challenge for the future will be to achieve photolytic liberation of carbon monoxide by near-IR excitation in the phototherapeutic window of the cell. Different ways how this goal might be achieved are discussed. © 2011 Elsevier B.V. All rights reserved.


Grinberg L.T.,University of California at San Francisco | Heinsen H.,University of Wurzburg
Journal of the Neurological Sciences | Year: 2010

To date, there are no widely accepted neuropathological criteria for vascular dementia, although creating such a standard is ranked high on the wish list of all the researchers in this field. Such criteria would make it possible to perform large multicentre clinicopathological studies and, consequently, to better understand which, how, and where vascular brain lesions lead to cognitive decline, as it is possible to do in Alzheimer's disease or Parkinson's disease. However, a major obstacle in the standardization of diagnosis is the fact that vascular brain lesions are a large group comprising heterogeneous changes that have different pathogeneses. Although it is accepted that some kinds of vascular changes cause cognitive impairment, it is not uncommon to find reports of the assumed same histological changes in control subjects. An indispensable first step in the unequivocal establishment of neuropathological criteria is to uniform the definitions used for each one of the lesions, preferably based on its pathogenesis. In the present, non-standardized state of ambiguity, a given lesion is designated by different names between and within the clinical, radiological, and pathological settings, and several definitions simply overlap. Before attempting to create new criteria, a multidisciplinary group-task is urged to identify and minimize the uncontrolled proliferation of definitions. Only then, it will be possible to advance the understanding of how vascular brain changes affect cognition. © 2010 Elsevier B.V. All rights reserved.


Czogalla K.J.,University of Bonn | Biswas A.,University of Bonn | Rost S.,University of Wurzburg | Watzka M.,University of Bonn | Oldenburg J.,University of Bonn
Blood | Year: 2014

Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) is an enzyme localized to the endoplasmic reticulum (ER) membrane. VKORC1 catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K and to vitamin K hydroquinone, the latter required by the enzyme γ-carboxylase for γ-carboxylation of all vitamin K-dependent (VKD) proteins. Until now, only 1 human VKORC1 mutation, p.Arg98Trp, is known to cause combined deficiency of VKD clotting factors type 2 (VKCFD2), a disease phenotype reported in 3 unrelated families. VKCFD2 patients suffer from spontaneous bleeding episodes because of decreased levels of γ-carboxylated VKD clotting factors. Daily supraphysiological vitamin K supplementation restores clotting for VKCFD2 patients and results in high serum levels of vitamin K 2,3-epoxide, suggesting that supplemented vitamin K is reduced in vivo. Although the p.Arg98Trp mutation results in reduced vitamin K2,3-epoxide reductase activity, the molecular mechanism underlying this pathophysiology is unknown. Using a combination of in silico analysis and confocal microscopy, we demonstrate for the first time that VKORC1:p.Arg98Trp disrupts a di-arginine ER retention motif resulting in 20% ER colocalization only. As a consequence, VKORC1 exits the ER membraneby cellular quality control systems and results in the observed VKCFD2 phenotype. © 2014 by The American Society of Hematology.


Werner H.,University of Wurzburg
Angewandte Chemie - International Edition | Year: 2014

Peter L. Pauson passed away at the age of 88 on December 10, 2013. He was well-known worldwide as one of the discoverers of ferrocene and the Pauson-Khand reaction. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kambeitz J.,Ludwig Maximilians University of Munich | Romanos M.,University of Wurzburg | Ettinger U.,University of Bonn
Pharmacogenomics Journal | Year: 2014

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent childhood-onset neuropsychiatric disorder. Treatment with methylphenidate, which blocks dopamine and noradrenaline transporters, is clinically efficacious in reducing the symptoms of ADHD. However, a considerable proportion of patients show no or only insufficient response to methylphenidate. Following a pharmacogenetic approach, a number of studies have suggested that heterogeneity in treatment response across subjects might to some extent be due to genetic factors. In particular, a variable number tandem repeat (VNTR) polymorphism in the 3′ untranslated region of the SLC6A3 gene, which codes for the dopamine transporter, has been considered as a predictor of treatment success. However, the literature has so far been inconsistent. Here we present results of a meta-analysis of studies investigating the moderating effect of the SLC6A3 VNTR on response to methylphenidate treatment in subjects with ADHD. Outcome measures from 16 studies including data from 1572 subjects were entered into a random-effects model. There was no significant summary effect for the SLC6A3 VNTR on the response to methylphenidate treatment (P>0.5) and no effect on specific symptom dimensions of hyperactivity/impulsivity and inattention (all P>0.2). However, in a subanalysis of naturalistic trials, we observed a significant effect of d=-0.36 (P=0.03), indicating that 10R homozygotes show less improvement in symptoms following treatment than the non-10/10 carriers. This meta-analysis indicates that SLC6A3 VNTR is not a reliable predictor of methylphenidate treatment success in ADHD. Our study leaves unanswered the question of whether other genetic polymorphisms or nongenetic factors may contribute to the observed heterogeneity in treatment response across ADHD subjects. © 2014 Macmillan Publishers Limited All rights reserved.


Nguyen T.N.,University of Connecticut Health Center | Muller L.S.M.,University of Connecticut Health Center | Park S.H.,University of Connecticut Health Center | Siegel T.N.,University of Wurzburg | Gunzl A.,University of Connecticut Health Center
Nucleic Acids Research | Year: 2014

Monoallelic expression within a gene family is found in pathogens exhibiting antigenic variation and in mammalian olfactory neurons. Trypanosoma brucei, a lethal parasite living in the human bloodstream, expresses variant surface glycoprotein (VSG) from 1 of 15 bloodstream expression sites (BESs) by virtue of a multifunctional RNA polymerase I. The active BES is transcribed in an extranucleolar compartment termed the expression site body (ESB), whereas silent BESs, located elsewhere within the nucleus, are repressed epigenetically. The regulatory mechanisms, however, are poorly understood. Here we show that two essential subunits of the basal class I transcription factor A (CITFA) predominantly occupied the promoter of the active BES relative to that of a silent BES, a phenotype that was maintained after switching BESs in situ. In these experiments, high promoter occupancy of CITFA was coupled to high levels of both promoter-proximal RNA abundance and RNA polymerase I occupancy. Accordingly, fluorescently tagged CITFA-7 was concentrated in the nucleolus and the ESB. Because a ChIP-seq analysis found that along the entire BES, CITFA-7 is specifically enriched only at the promoter, our data strongly indicate that monoallelic BES transcription is activated by a mechanism that functions at the level of transcription initiation. © The Author(s) 2013.


Larsen M.,University of Wurzburg
European Journal of Human Genetics | Year: 2016

The myotonic dystrophies (DMs) are the most common inherited muscular disorders in adults. In most of the cases, the disease is caused by (CTG)n/(CCTG)n repeat expansions (EXPs) in non-coding regions of the genes DMPK (dystrophia myotonica-protein kinase) and CNBP (CCHC-type zinc-finger nucleic acid-binding protein). The EXP is transcribed into mutant RNAs, which provoke a common pathomechanism that is characterized by misexpression and mis-splicing. In this study, we screened 138 patients with typical clinical features of DM being negative for EXP in the known genes. We sequenced DMPK and CNBP – associated with DM, as well as CELF1 (CUGBP, Elav-like family member 1) and MBNL1 (muscleblind-like splicing regulator 1) – associated with the pathomechanism of DM, for pathogenic variants, addressing the question whether defects in other genes could cause a DM-like phenotype. We identified variants in three unrelated patients in the MBNL1 gene, two of them were heterozygous missense mutations and one an in-frame deletion of three amino acids. The variants were located in different conserved regions of the protein. The missense mutations were classified as potentially pathogenic by prediction tools. Analysis of MBNL1 splice target genes was carried out for one of the patients using RNA from peripheral blood leukocytes (PBL). Analysis of six genes known to show mis-splicing in the skeletal muscle gave no informative results on the effect of this variant when tested in PBL. The association of these variants with the DM phenotype therefore remains unconfirmed, but we hope that in view of the key role of MBNL1 in DM pathogenesis our observations may foster further studies in this direction.European Journal of Human Genetics advance online publication, 25 May 2016; doi:10.1038/ejhg.2016.41. © 2016 Macmillan Publishers Limited


Klein I.,University of Wurzburg | Gessner U.,German Aerospace Center | Kuenzer C.,German Aerospace Center
Applied Geography | Year: 2012

In Central Asia major alterations in land use and land cover occurred in the past decades due to political collapse of the Soviet Union, human forces, and climate change. In this context accurate land cover information for the region of Central Asia is important. In this study we present a classification approach with implemented C5.0 algorithm addressing regional land cover characteristics of Central Asia. The classification is performed on seasonal features derived from MODIS time-series for the years 2001 and 2009, which allows us to analyse possible land cover and land use changes. Training and validation are based on a reference dataset collected from high resolution remote sensing data. The overall accuracy of both classifications is above 90%. The results show some significant changes between both years in different land cover classes. Human induced alterations of water bodies, variability in sparsely vegetated areas due to seasonal precipitation and forest loss caused by forest fires and logging are exemplarily depicted and discussed in this study. © 2012 Elsevier Ltd.


Scheper J.,Wageningen University | Holzschuh A.,University of Wurzburg | Kuussaari M.,Finnish Environment Institute | Potts S.G.,University of Reading | And 3 more authors.
Ecology Letters | Year: 2013

In Europe, agri-environmental schemes (AES) have been introduced in response to concerns about farmland biodiversity declines. Yet, as AES have delivered variable results, a better understanding of what determines their success or failure is urgently needed. Focusing on pollinating insects, we quantitatively reviewed how environmental factors affect the effectiveness of AES. Our results suggest that the ecological contrast in floral resources created by schemes drives the response of pollinators to AES but that this response is moderated by landscape context and farmland type, with more positive responses in croplands (vs. grasslands) located in simple (vs. cleared or complex) landscapes. These findings inform us how to promote pollinators and associated pollination services in species-poor landscapes. They do not, however, present viable strategies to mitigate loss of threatened or endangered species. This indicates that the objectives and design of AES should distinguish more clearly between biodiversity conservation and delivery of ecosystem services. © 2013 John Wiley & Sons Ltd/CNRS.


Spindler V.,Ludwig Maximilians University of Munich | Dehner C.,Ludwig Maximilians University of Munich | Hubner S.,University of Wurzburg | Waschke J.,Ludwig Maximilians University of Munich
Journal of Investigative Dermatology | Year: 2014

Plakoglobin (Pg) and desmoplakin (DP) are adapter proteins within the desmosome, providing a mechanical link between desmosomal cadherins as transmembrane adhesion molecules and the intermediate filament cytoskeleton. As in the severe skin blistering disease pemphigus, autoantibodies against desmosomal adhesion molecules induce loss of keratinocyte cohesion at least in part via p38 mitogen-activated protein kinase (p38MAPK) activation and depletion of desmosomal components, we evaluated the roles of Pg and DP in the p38MAPK-dependent loss of cell adhesion. Silencing of either Pg or DP reduced cohesion of cultured human keratinocytes in dissociation assays. However, Pg but not DP silencing caused activation of p38MAPK-dependent keratin filament collapse and cell dissociation. Interestingly, extranuclear but not nuclear Pg rescued loss of cell adhesion and keratin retraction. In line with this, Pg regulated the levels of the desmosomal adhesion molecule desmoglein 3 and tethered p38MAPK to desmosomal complexes. Our data demonstrate a role of extranuclear Pg in controlling cell adhesion via p38MAPK-dependent regulation of keratin filament organization. © 2014 The Society for Investigative Dermatology.


King S.F.,University of Southampton | Morisi S.,University of Wurzburg | Peinado E.,National Institute of Nuclear Physics, Italy | Valle J.W.F.,University of Valencia
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

We propose a realistic A4 extension of the Standard Model involving a particular quark-lepton mass relation, namely that the ratio of the third family mass to the geometric mean of the first and second family masses are equal for down-type quarks and charged leptons. This relation, which is approximately renormalization group invariant, is usually regarded as arising from the Georgi-Jarlskog relations, but in the present model there is no unification group or supersymmetry. In the neutrino sector we propose a simple modification of the so-called Zee-Wolfenstein mass matrix pattern which allows an acceptable reactor angle along with a deviation of the atmospheric and solar angles from their bi-maximal values. Quark masses, mixing angles and CP violation are well described by a numerical fit. © 2013 Elsevier B.V.


Budich J.C.,University of Stockholm | Trauzettel B.,University of Wurzburg
New Journal of Physics | Year: 2013

We represent the ℤ2 topological invariant characterizing a one-dimensional topological superconductor using a WessZuminoWitten dimensional extension. The invariant is formulated in terms of the single-particle Greens function which allows us to classify interacting systems. Employing a recently proposed generalized Berry curvature method, the topological invariant is represented independent of the extra dimension requiring only the single-particle Greens function at zero frequency of the interacting system. Furthermore, a modified twisted boundary conditions approach is used to rigorously define the topological invariant for disordered interacting systems.


Schenk W.A.,University of Wurzburg
Dalton Transactions | Year: 2011

The sulfur oxides SO, SO2 and SO3, and thioformaldehyde H2CS and its oxides H2CSO and H 2CSO2 form stable coordination compounds with a range of transition metals. The complexes have a rich chemistry which differs markedly from that of the free ligands. Typical reactions involve electrophilic additions, nucleophilic additions and cycloadditions. The complexes can be used as synthons to incorporate these small molecules as building blocks into larger structures. © 2011 The Royal Society of Chemistry.


Holzgrabe U.,University of Wurzburg | Malet-Martino M.,French National Center for Scientific Research
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

Counterfeiting of products is a global problem. As long as clothes, clocks, leather wear, etc. are faked there is no danger, but when it comes to drugs, counterfeiting can be life-threatening. In the last years sub-standard active pharmaceutical ingredients (APIs) were found more often even though the use of the quality-ensuring methods of international pharmacopoeias should have detected additional impurities and the low content of the API. Methods orthogonal to the separating methods used in the pharmacopoeias are necessary to find counterfeits. Beside Raman and NIR spectroscopies as well as powder X-ray analysis, NMR spectroscopy being a primary ratio method of measurement is highly suitable to identify and quantify a drug and its related substances as well as to recognize a drug of sub-standard quality. DOSY experiments are suitable to identify the ingredients of formulations and therefore to identify wrong and/or additional ingredients. This review gives an overview of the application of quantitative NMR spectroscopy and DOSY NMR in anticounterfeiting. © 2010 Elsevier B.V.


Fischbach W.,University of Wurzburg
Best Practice and Research: Clinical Gastroenterology | Year: 2014

Gastrointestinal lymphoma represent a heterogenous group with differences in pathogenesis, treatment and prognosis. Gastric MALT lymphoma is the most common entity. Helicobacter pylori has been identified as its decisive pathogenetic factor. Once a definitive diagnosis has been established a staging procedure is obligatory for defining the stage of disease. H. pylori eradication is the treatment of choice in all MALT lymphoma patients being infected by the bacterium. In some 70e80% of patients with stages I/II complete regression of the lymphoma will develop after successful eradication of H. pylori. Another 20% of patients will reveal minimal histological residuals after eradication. They can be successfully managed by a watch-and-wait strategy if initial endoscopic abnormalities disappear. At present, it is unclear if this strategy can be also offered to patients with persisting minimal endoscopic abnormalities. Why eradication therapy is effective in some patients with negative H. pylori status is highly speculative at present. Non-responders to H. pylori therapy are transferrred to radiotherapy in stages I/II or to immuno-chemotherapy in stages III/IV. © 2014 Published by Elsevier Ltd.


Braxmeier-Even N.,University of Wurzburg | Olla S.,University of Paris Dauphine
Archive for Rational Mechanics and Analysis | Year: 2014

We study the hyperbolic scaling limit for a chain of N coupled anharmonic oscillators. The chain is attached to a point on the left and there is a force (tension) τ acting on the right. In order to provide good ergodic properties to the system, we perturb the Hamiltonian dynamics with random local exchanges of velocities between the particles, so that momentum and energy are locally conserved. We prove that in the macroscopic limit the distributions of the elongation, momentum and energy converge to the solution of the Euler system of equations in the smooth regime. © 2014 Springer-Verlag Berlin Heidelberg.


Crutzen R.,Maastricht University | Goritz A.S.,University of Wurzburg
BMC Public Health | Year: 2010

Background: These studies sought to investigate the relation between social desirability and self-reported health risk behaviors (e.g., alcohol use, drug use, smoking) in web-based research. Methods. Three longitudinal studies (Study 1: N = 5612, 51% women; Study 2: N = 619, 60%; Study 3: N = 846, 59%) among randomly selected members of two online panels (Dutch; German) using several social desirability measures (Marlowe-Crowne Scale; Balanced Inventory of Desirable Responding; The Social Desirability Scale-17) were conducted. Results. Social desirability was not associated with self-reported current behavior or behavior frequency. Socio-demographics (age; sex; education) did not moderate the effect of social desirability on self-reported measures regarding health risk behaviors. Conclusions. The studies at hand provided no convincing evidence to throw doubt on the usefulness of the Internet as a medium to collect self-reports on health risk behaviors. © 2010 Crutzen and Göritz; licensee BioMed Central Ltd.


Gogolin C.,University of Wurzburg
Physical Review E - Statistical, Nonlinear, and Soft Matter Physics | Year: 2010

We investigate decoherence and equilibration in the experimentally relevant situation of weak coupling to an environment. We consider small subsystems of large closed quantum systems that evolve according to the von Neumann equation. Without approximations and without making any special assumptions on the form of the interaction we prove that, for almost all initial states and almost all times, the off-diagonal elements of the density matrix of the subsystem in the eigenbasis of its local Hamiltonian must be small whenever the energy difference of the corresponding eigenstates is larger than the interaction energy. This proves that decoherence with respect to the local energy eigenbasis is a natural property of weakly interacting quantum systems. © 2010 The American Physical Society.


Zeplin P.H.,University of Wurzburg
Annals of Plastic Surgery | Year: 2012

Burn scar formations can cause disfiguration and loss of dermal function. The purpose of this study was to examine whether application of modified silicone gel sheets with an antifibrotic drug halofuginone-eluting hybrid surface produce an effect on scar development. There were a total of 2 animal groups. The athymic nude mice (nu/nu) of both groups underwent transplantation of full-thickness human skin grafts onto their backs and setting of partial thickness burn injury. The status of local scar development was observed over a period of 3 months after the application of silicone gel sheets and also after application of surface-modified halofuginone-eluting silicone gel sheets. Subsequently, via real-time polymerase chain reaction, the cDNA levels from key mediators of scar formation (transforming growth factor beta, COL1A1, connective tissue growth factor, fibroblast growth factor 2, matrix metalloproteinase 2, matrix metalloproteinase 9) were established and statistically evaluated. In comparison with uncoated silicone gel sheets, the application of halofuginone-eluting silicone gel sheets lead to a significant difference in gene expression activity in scar tissue. Halofuginone-eluting hybrid surface silicone gel sheets significantly increase the antiscarring effect of adhesive silicone gel sheets by deceleration and downregulation of scar development by normalization of the expression activity. Copyright © 2012 by Lippincott Williams & Wilkins.


Bochman M.L.,Princeton University | Paeschke K.,University of Wurzburg | Zakian V.A.,Princeton University
Nature Reviews Genetics | Year: 2012

In addition to the canonical double helix, DNA can fold into various other inter-and intramolecular secondary structures. Although many such structures were long thought to be in vitro artefacts, bioinformatics demonstrates that DNA sequences capable of forming these structures are conserved throughout evolution, suggesting the existence of non-B-form DNA in vivo. In addition, genes whose products promote formation or resolution of these structures are found in diverse organisms, and a growing body of work suggests that the resolution of DNA secondary structures is critical for genome integrity. This Review focuses on emerging evidence relating to the characteristics of G-quadruplex structures and the possible influence of such structures on genomic stability and cellular processes, such as transcription. © 2012 Macmillan Publishers Limited. All rights reserved.


Heineke J.,Medizinische Hochschule Hanover | Ritter O.,University of Wurzburg
Journal of Molecular and Cellular Cardiology | Year: 2012

The serine-threonine phosphatase calcineurin is activated in cardiac myocytes in the diseased heart and induces pathological hypertrophy. Calcineurin activity is mainly triggered by calcium/calmodulin binding but also through calpain mediated cleavage. How controlled calcineurin activation is possible in cardiac myocytes, which typically show a 10-fold difference in cytosolic calcium concentration with every heartbeat, has remained enigmatic. It is now emerging that calcineurin activation and signaling occur in subcellular microdomains, in which it is brought together with target proteins and exceedingly high concentrations of calcium in order to induce downstream signaling. We review current evidence of subcellular calcineurin mainly at the sarcolemma and the nucleus, but also in association with the sarcoplasmic reticulum and mitochondria. We also suggest that knowledge about subcellular signaling could help to develop inhibitors of calcineurin in specific microdomains to avoid side-effects that may arise from complete calcineurin inhibition. © 2011 Elsevier Ltd.


Kanzow C.,University of Wurzburg
Mathematical Programming | Year: 2016

The multiplier-penalty approach is one of the classical methods for the solution of constrained optimization problems. This method was generalized to the solution of quasi-variational inequalities by Pang and Fukushima (Comput Manag Sci 2:21–56, 2005). Based on the recent improvements achieved for the multiplier-penalty approach for optimization, we generalize the method by Pang and Fukushima for quasi-variational inequalities in several respects: (a) We allow to compute inexact KKT-points of the resulting subproblems; (b) We improve the existing convergence theory; (c) We investigate some special classes of quasi-variational inequalities where the resulting subproblems turn out to be easy to solve. Some numerical results indicate that the corresponding method works quite reliable in practice. © 2016 Springer-Verlag Berlin Heidelberg and Mathematical Optimization Society


Langenfeld U.,University of Wurzburg | Moch S.-O.,German Electron Synchrotron | Pfoh T.,German Electron Synchrotron
Journal of High Energy Physics | Year: 2012

We present the complete threshold enhanced predictions in QCD for the total cross section of gluino pair production at hadron colliders at next-to-next-to-leading order. Thanks to the computation of the required one-loop hard matching coeficients our results are accurate to the next-to-next-to-leading logarithm. In a brief phenomenological study we provide predictions for the total hadronic cross sections at the LHC and we discuss the uncertainties arising from scale variations and the parton distribution functions. © SISSA 2012.


Xiao J.,Shanghai Normal University | Xiao J.,University of Wurzburg | Kai G.,Shanghai Normal University | Yamamoto K.,Okayama Prefectural University | Chen X.,Central South University
Critical Reviews in Food Science and Nutrition | Year: 2013

The dietary polyphenols as α-glucosidases inhibitors have attracted great interest among researchers. The aim of this review is to give an overview of the research reports on the structure-activity relationship of dietary polyphenols inhibiting α-glucosidases. The molecular structures that influence the inhibition are the following: (1) The hydroxylation and galloylation of flavonoids including catechins improve the inhibitory activity. (2) The glycosylation of hyroxyl group and hydrogenation of the C2=C3 double bond on flavonoids weaken the inhibition. (3) However, cyaniding glycosides show higher inhibition against than cyanidin. Proanthocyanidins oligomers exhibit a stronger inhibitory activity than their polymers. (4) The hydroxylation on B ring and the glycosylation of stilbenes reduce the inhibitory activity. (5) Caffeoylquinic acids display strong inhibition against α-glucosidases. However, hydroxycinnamic acid, ferulic acid, and gallic acid hardly inhibited α-glucosidases. (6) The coupled galloyl structures attached to C-3 and C-6 of the 4C1 glucose core of ellagitanin gave basic inhibitory activity. (7) The mono-glycosylation of chalcones slightly lowers the inhibition. However, the diglycosylation of chalcones significantly decreased the activity. © 2013 Copyright Taylor and Francis Group, LLC.


Nordbeck P.,University of Wurzburg
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine | Year: 2011

Implanted medical devices such as cardiac pacemakers pose a potential hazard in magnetic resonance imaging. Electromagnetic fields have been shown to cause severe radio frequency-induced tissue heating in some cases. Imaging exclusion zones have been proposed as an instrument to reduce patient risk. The purpose of this study was to further assess the impact of the imaging landmark on the risk for unintended implant heating by measuring the radio frequency-induced electric fields in a body phantom under several imaging conditions at 1.5T. The results show that global radio frequency-induced coupling is highest with the torso centered along the superior-inferior direction of the transmit coil. The induced E-fields inside the body shift when changing body positioning, reducing both global and local radio frequency coupling if body and/or conductive implant are moved out from the transmit coil center along the z-direction. Adequate selection of magnetic resonance imaging landmark can significantly reduce potential hazards in patients with implanted medical devices. © 2010 Wiley-Liss, Inc.


BACKGROUND: Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease predominantly occurring in young men. Cardinal symptoms are pain and perineal swelling. Although several risk factors are described in the literature, the exact etiology of penile thrombosis remains unclear in most cases. MRI or ultrasound (US) is usually used for diagnosing this condition.CASE PRESENTATION: We report a case of penile thrombosis after left-sided varicocele ligature in a young patient. The diagnosis was established using contrast-enhanced ultrasound (CEUS) and was confirmed by contrast-enhanced magnetic resonance imaging (ceMRI). Successful conservative treatment consisted of systemic anticoagulation using low molecular weight heparin and acetylsalicylic acid.CONCLUSION: PSTCC is a rare condition in young men and appears with massive pain and perineal swelling. In case of suspected PSTCC utilization of CEUS may be of diagnostic benefit.


Hall J.,Simon Fraser University | Wagner M.,University of Wurzburg
Business Strategy and the Environment | Year: 2012

Innovation has been widely regarded as a panacea for sustainable development, but there remains considerable uncertainty about how it will lead to a more sustainable society. We analyze the role of innovation and business models for the link between the integration of sustainable management with other corporate functions and the economic and environmental performance of companies. Drawing on survey data in the manufacturing sector, we apply structural equation modeling to compare differences between business models and the role of different stakeholder groups in a moderation analysis. We find a positive association of the integration of strategic issues and environmental management with the economic and environmental performance of firms. The results also suggest differences in the link between integration and economic and environmental performance, respectively, depending on the type of business model or innovation pursued, and that secondary stakeholders influence sustainability integration. © 2011 John Wiley & Sons, Ltd and ERP Environment.


Gupta K.J.,Max Planck Institute of Molecular Plant Physiology | Fernie A.R.,Max Planck Institute of Molecular Plant Physiology | Kaiser W.M.,University of Wurzburg | van Dongen J.T.,Max Planck Institute of Molecular Plant Physiology
Trends in Plant Science | Year: 2011

Nitric oxide (NO) is widely recognized for its role as signaling compound. However, the metabolic mechanisms that determine changes in the level of NO in plants are only poorly understood, despite this knowledge being crucial to understanding the signal function of NO. To date, at least seven possible pathways of NO biosynthesis have been described for plants, although the molecular and enzymatic components are resolved for only one of these. Currently, this represents the most significant bottleneck for NO research. In this review, we provide an overview of the multiplicity of NO production and scavenging pathways in plants. Furthermore, we discuss which areas should be focused on in future studies to investigate the origin of fluctuations in the level of NO in plants. © 2010 Elsevier Ltd.


Waagan K.,University of Maryland University College | Federrath C.,University of Heidelberg | Klingenberg C.,University of Wurzburg
Journal of Computational Physics | Year: 2011

The ideal MHD equations are a central model in astrophysics, and their solution relies upon stable numerical schemes. We present an implementation of a new method, which possesses excellent stability properties. Numerical tests demonstrate that the theoretical stability properties are valid in practice with negligible compromises to accuracy. The result is a highly robust scheme with state-of-the-art efficiency. The scheme's robustness is due to entropy stability, positivity and properly discretised Powell terms. The implementation takes the form of a modification of the MHD module in the FLASH code, an adaptive mesh refinement code. We compare the new scheme with the standard FLASH implementation for MHD. Results show comparable accuracy to standard FLASH with the Roe solver, but highly improved efficiency and stability, particularly for high Mach number flows and low plasma β. The tests include 1D shock tubes, 2D instabilities and highly supersonic, 3D turbulence. We consider turbulent flows with RMS sonic Mach numbers up to 10, typical of gas flows in the interstellar medium. We investigate both strong initial magnetic fields and magnetic field amplification by the turbulent dynamo from extremely high plasma β. The energy spectra show a reasonable decrease in dissipation with grid refinement, and at a resolution of 5123 grid cells we identify a narrow inertial range with the expected power law scaling. The turbulent dynamo exhibits exponential growth of magnetic pressure, with the growth rate higher from solenoidal forcing than from compressive forcing. Two versions of the new scheme are presented, using relaxation-based 3-wave and 5-wave approximate Riemann solvers, respectively. The 5-wave solver is more accurate in some cases, and its computational cost is close to the 3-wave solver. © 2011 Elsevier Inc.


Lopez D.,University of Wurzburg | Kolter R.,Harvard University
Chemical Reviews | Year: 2011

The increasingly frequent failure of some of the antibiotics to control many previously treatable infections has led to the investigation of the mechanisms responsible for such resistance. The production of antibiotics commonly occurs when cells reach stationary phase, and often, relatively high cell densities are required for robust antibiotic production. Bacteria count population members in a quorum-sensing process by releasing self-produced signaling molecules or autoinducers (AI) that accumulate externally. When the autoinducing molecules accumulate in the medium above a certain threshold, they trigger the quorum-sensing response. The acyl homoserine lactones (AHL) are an important class of autoinducers that contain structural differences in their aliphatic tails in Gram-negative bacteria. Cell signaling and cell density are especially important in the formation of tightly packed, spatially organized biofilms. These bacterial communities are often attached to surfaces and encased in an extracellular matrix normally produced by the bacteria themselves.


Rethwilm A.,University of Wurzburg
Medical Microbiology and Immunology | Year: 2010

One of the most fascinating areas in retrovirology is the study of foamy viruses (FVs), because these viruses appear to do everything that is common to all other retroviruses differently. FVs have found a completely new way to propagate their genome. And they do this extremely successfully because most of wild non-human primates, felines, bovines, equines, and small ruminants are likely to be non-pathogenically infected. The success of FVs can also be viewed from a different angle, since they replicate very conservatively and do not need to shape their genotypic and phenotypic makeup every now and then. The elucidation of the underlying basic mechanisms of the FV replication strategy is the topic of this review. © 2010 Springer-Verlag.


Quinkler M.,Charite - Medical University of Berlin | Hahner S.,University of Wurzburg
Clinical Endocrinology | Year: 2012

Primary adrenal insufficiency is treated with glucocorticoid and mineralocorticoid replacement therapy. Recent data revealed that health-related quality of life in adrenal insufficiency is impaired in many patients and that patients with adrenal insufficiency are also threatened by an increased mortality and morbidity. This may be caused by inadequate glucocortiocid therapy and adrenal crisis. Therefore, the optimization of hormone replacement therapy remains one of the most challenging tasks in endocrinology because it is largely based on clinical grounds because of the lack of objective assessment tools. This article provides answers to the important daily clinical questions, such as correct dose finding, dose adaptation in special situations, e g, pregnancy, improvement of quality of life and measures for protection from adrenal crisis. Other important aspects discussed are side effects of glucocortiocid replacement therapy and interactions with other drugs. © 2011 Blackwell Publishing Ltd.


Wyler Von Ballmoos M.C.,Medical College of Wisconsin | Haring B.,University of Wurzburg | Sacks F.M.,Harvard University
Journal of Clinical Lipidology | Year: 2015

Background Apolipoprotein CIII (apoC-III) is an atherogenic protein found on HDL, VLDL and LDL. Objective The objective of this study is to review the literature on the association of blood apoC-III level with cardiovascular events and the dose-response relationship for this association. Methods and results MEDLINE, EMBASE, BIOSIS, CINAHL, Clinicaltrials.gov, grey-literature sources, contact with investigators, and reference lists of studies, without language restrictions, were reviewed. Twelve studies (5 retrospective and 7 prospective) with a total of 3163 cases of cardiovascular events met inclusion criteria for this systematic review. The pooled standardized mean difference showed significantly higher levels of apoC-III in the non-HDL fraction of plasma (representing apoC-III in VLDL and LDL) in those with cardiovascular disease compared with controls; no difference for apoC-III levels in HDL; and, a trend toward higher total plasma apoC-III in the cases. Pooled risk estimates from the meta-analysis were 2.48 (1.48-4.32; non-HDL apoC-III), 1.09 (0.65-1.82; HDL apoC-III), and 1.33 (1.07-1.66; total apoC-III) for a cardiovascular event with a 5-mg/dL increase in apoC-III. Conclusions The current body of literature includes several methodologically sound studies that together provide consistent evidence for an association of cardiovascular events with blood apoC-III level in total plasma or in VLDL and LDL. More data are needed to determine importance of levels of apoC-III in specific lipoproteins for cardiovascular risk assessment and management and to elucidate the interaction between triglycerides and apoC-III in relation to risk of cardiovascular disease. © 2015 National Lipid Association. All rights reserved.


Waight P.A.,Public Health England | Andrews N.J.,Public Health England | Ladhani S.N.,Public Health England | Sheppard C.L.,Public Health England | And 3 more authors.
The Lancet Infectious Diseases | Year: 2015

Background: The 13-valent pneumococcal conjugate vaccine (PCV13) protects against key serotypes that increased after routine immunisation with the seven-valent vaccine (PCV7), but its potential for herd protection and serotype replacement is uncertain. The aim of this study was to analyse the effect of the 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in England and Wales 4 years after its introduction. Methods: We used a national dataset of electronically reported and serotyped invasive pneumococcal disease cases in England and Wales to estimate incidence rate ratios (IRRs) for vaccine and non-vaccine type invasive pneumococcal disease between July, 2013, and June, 2014, versus the pre-PCV13 and pre-PCV7 baseline. Incidence rates were corrected for missing serotype data and changes in surveillance sensitivity over time. An over-dispersed Poisson model was used to estimate IRRs and confidence intervals. Findings: Incidence of invasive pneumococcal disease in the epidemiological year 2013/14 decreased by 32% compared with the pre-PCV13 baseline (incidence 10·14 per 100 000 in 2008-10 vs 6·85 per 100 000 in 2013/14; IRR 0·68, 95% CI 0·64-0·72). This was due to an 86% reduction of the serotypes covered by PCV7 (1·46 vs 0·20 per 100 000; IRR 0·14, 0·10-0·18) and a 69% reduction of the additional six serotypes covered by PCV13 (4·48 vs 1·40 per 100 000; IRR 0·31, 0·28-0·35). When compared with the pre-PCV7 baseline, there was a 56% overall reduction in invasive pneumococcal disease (15·63 vs 6·85 per 100 000; IRR 0·44, 95% CI 0·43-0·47). Compared with the pre-PCV13 baseline, the incidence of non-PCV13 serotypes increased (incidence all ages 4·19 vs 5·25 per 100 000; IRR 1·25, 95% CI 1·17-1·35) due to increases across a broad range of serotypes in children younger than 5 years and in people aged 45 years or more. In children younger than 5 years, incidence of non-PCV13 serotypes in 2013/14 was higher than in 2012/13 (age <2 years: 12·03 vs 10·83 per 100 000; age 2-4 years: 4·08 vs 3·63 per 100 000). Interpretation: 8 years of PCV use in England and Wales has reduced the overall incidence of invasive pneumococcal disease by more than 50%. The herd protection induced by PCV7 is continuing, and similar indirect protection is occurring from the additional serotypes covered by PCV13. There is, however, evidence of increasing invasive pneumococcal disease due to non-PCV13 serotypes, particularly in children younger than 5 years in 2014. If this increase continues, the maximum benefit of the PCV13 programme in children might already have been achieved. Funding: Public Health England funds national surveillance of invasive pneumococcal disease. © 2015 Elsevier Ltd.


Alveolar echinococcosis, one of the most serious and life-threatening zoonoses in the world, is caused by the metacestode larval stage of the fox-tapeworm Echinococcus multilocularis. Mostly due to its accessibility to in vitro cultivation, this parasite has recently evolved into an experimental model system to study larval cestode development and associated host-parasite interaction mechanisms. Respective advances include the establishment of axenic in vitro cultivation systems for parasite larvae as well as culture systems by which the early development of metacestode vesicles from totipotent parasite stem cells can be reconstituted under controlled laboratory conditions. A series of evolutionarily conserved signalling molecules of the insulin, epidermal growth factor and transforming growth factor-β pathways that are able to functionally interact with corresponding host cytokines have been described in E. multilocularis and most likely play a crucial role in parasite development within the liver of the intermediate host. Furthermore, a whole genome sequencing project has been initiated by which a comprehensive picture on E. multilocularis cell-cell communication systems will be available in due time, including information on parasite cytokines that are secreted towards host tissue and thus might affect the immune response. In this article, an overview of our current picture on Echinococcus signalling systems will be given, and the potential to exploit these pathways as targets for anti-parasitic chemotherapy will be discussed. © 2010 Springer-Verlag.


Morschhauser J.,University of Wurzburg
Medical Microbiology and Immunology | Year: 2010

The yeast Candida albicans is part of the microflora in most healthy people, but can become a pathogen when host defenses are compromised. The phenotypic plasticity of C. albicans, which includes switching between different morphologies, contributes to its ability to colonize and infect virtually all body locations. A particularly fascinating developmental program is white-opaque switching, a reversible transition between the normal yeast morphology (white) and an elongated cell type (opaque), which is the mating-competent form of this fungus. Although opaque cells are much less able than white cells to cause a systemic infection, they are better adapted for colonization of specific host niches, like skin. White-opaque switching is controlled by the mating type locus (MTL), which in most C. albicans strains exists in two alleles, MTL a and MTLα. These strains produce a heterodimeric repressor, a1-α2, which suppresses switching to the opaque phase by inhibiting expression of the master regulator Wor1. Loss of MTL heterozygosity relieves this repression, a mechanism that ensures that only MTL homozygous cells can switch to the mating-competent opaque form. Several transcriptional feedback loops, including positive autoregulation of Wor1, result in bistable expression of the master regulator (low in white and high in opaque cells) and epigenetic inheritance of the two phases. White-opaque switching occurs stochastically at a low frequency, but certain environmental conditions can drive the switch from one phase to the other by affecting either the activity of the transcriptional feedback loops or accumulation of Wor1 protein in a cell. Such environmental regulation of phenotypic switching may restrict mating to suitable host niches, while allowing a C. albicans population to withstand the various challenges encountered in different tissues. © 2010 Springer-Verlag.


Kirsch W.,University of Wurzburg
Acta Psychologica | Year: 2015

Previous research suggested that perception of spatial location is biased towards spatial goals of planned hand movements. In the present study I show that an analogous perceptual distortion can be observed if attention is paid to a spatial location in the absence of planning a hand movement. Participants judged the position of a target during preparation of a mouse movement, the end point of which could deviate from the target by a varying degree in Exp. 1. Judgments of target position were systematically affected by movement characteristics consistent with perceptual assimilation between the target and the planned movement goal. This effect was neither due to an impact of motor execution on judgments (Exp. 2) nor due to characteristics of the movement cues or of certain target positions (Exp. 3, Exp. 5A). When the task included deployment of attention to spatial positions (former movement goals) in preparation for a secondary perceptual task, an effect emerged that was comparable with the bias associated with movement planning (Exp. 4, Exp. 5B). These results indicate that visual distortions accompanying manipulations of variables related to action could be mediated by attentional mechanisms. © 2015 Elsevier B.V.


Upadhyay A.,Boston University | Earley A.,Tufts University | Lamont J.L.,Tufts University | Haynes S.,Tufts Medical Center | And 2 more authors.
Annals of Internal Medicine | Year: 2012

Background: Lipid-lowering therapy is not widely used in persons with chronic kidney disease (CKD) despite a high burden of dys- lipidemia and cardiovascular disease in this population. Purpose: To synthesize evidence examining the effect of lipid- lowering therapy on clinical outcomes in persons with CKD. Data Sources: MEDLINE, the Cochrane Central Register of Con- trolled Trials, and the Cochrane Database of Systematic Reviews from January 2000 through November 2011. Study Selection: Randomized, controlled trials (RCTs) comparing lipid-lowering therapy with control treatment in persons with CKD, including subgroup analyses of trials in the general population. Data Extraction: Abstracts were screened and data were extracted on study methodology, population, interventions, cardiovascular and kidney outcomes, and adverse events. Data were extracted by one author and confirmed by another. Study quality was deter- mined by consensus. Random-effects model meta-analyses were performed. Data Synthesis: 18 RCTs, all in adults, met the eligibility criteria. Five RCTs involved CKD populations, and 13 were CKD subgroup analyses from trials in the general population. Sixteen RCTs exam- ined statins, and 2 examined statins plus ezetimibe. Lipid-lowering therapy does not improve kidney outcomes but decreases the risk for cardiac mortality (pooled risk ratio [RR] from 6 trials, 0.82 [95% CI, 0.74 to 0.91]; P < 0.001), cardiovascular events (including revascularization) (pooled RR from 9 trials, 0.78 [CI, 0.71 to 0.86]; P < 0.001), and myocardial infarction (pooled RR from 9 trials, 0.74 [CI, 0.67 to 0.81]; P < 0.001). Significant benefit was also seen for all-cause mortality but was limited by a high degree of heterogeneity. No benefit was found for other cardiovascular out- comes. Rates of adverse events were similar between intervention and comparator groups. Limitations: Lack of data in children, heterogeneity among re- viewed studies, and the possibility of selective reporting of out- comes and adverse events. Conclusion: Lipid-lowering therapy decreases cardiac death and atherosclerosis-mediated cardiovascular events in persons with CKD. Primary Funding Source: Kidney Diseases: Improving Global Outcomes. © 2012 American College of Physicians.


Fernandez-Saiz V.,Max Planck Institute of Biochemistry | Fernandez-Saiz V.,TU Munich | Buchberger A.,Max Planck Institute of Biochemistry | Buchberger A.,University of Wurzburg
EMBO Reports | Year: 2010

The ubiquitin-selective chaperone p97 is involved in major proteolytic pathways of eukaryotic cells and has been implicated in several human proteinopathies. Moreover, mutations in p97 cause the disorder inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD). The molecular basis underlying impaired degradation and pathological aggregation of ubiquitinated proteins in IBMPFD is unknown. Here, we identify perturbed co-factor binding as a common defect of IBMPFD-causing mutant p97. We show that IBMPFD mutations induce conformational changes in the p97 N domain, the main binding site for regulatory co-factors. Consistently, mutant p97 proteins exhibit strongly altered co-factor interactions. Specifically, binding of the ubiquitin ligase E4B is reduced, whereas binding of ataxin 3 is enhanced, thus resembling the accumulation of mutant ataxin 3 on p97 in spinocerebellar ataxia type 3. Our results suggest that imbalanced co-factor binding to p97 is a key pathological feature of IBMPFD and potentially of other proteinopathies involving p97. © 2010 EUROPEEAN MoleEcular Biology Oorganization.


Neupert T.,Princeton University | Chamon C.,Boston University | Mudry C.,Paul Scherrer Institute | Thomale R.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2014

A scheme is proposed to construct integer and fractional topological quantum states of fermions in two spatial dimensions. We devise models for such states by coupling wires of nonchiral Luttinger liquids of electrons that are arranged in a periodic array. Which interwire couplings are allowed is dictated by symmetry and the compatibility criterion that they can simultaneously acquire a finite expectation value, opening a spectral gap between the ground state(s) and all excited states in the bulk. First, with these criteria at hand, we reproduce the tenfold classification table of integer topological insulators, where their stability against interactions becomes immediately transparent in the Luttinger liquid description. Second, we construct an example of a strongly interacting fermionic topological phase of matter with short-range entanglement that lies outside of the tenfold classification. Third, we expand the table to long-range entangled topological phases with intrinsic topological order and fractional excitations. © 2014 American Physical Society.


Vallat J.-M.,Limoges University Hospital Center | Sommer C.,University of Wurzburg | Magy L.,Limoges University Hospital Center
The Lancet Neurology | Year: 2010

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic neuropathy of supposed immune origin. Understanding of its pathophysiology has recently improved, although its causes remain unclear. The classic presentation of CIDP includes sensory and motor symptoms in the distal and proximal segments of the four limbs with areflexia, evolving over more than 8 weeks. Raised protein concentrations in CSF and heterogeneous slowing of nerve conduction are typical of the condition. In addition to this usual phenotype, distribution of symptoms, disease course, and disability can be heterogeneous, leading to underdiagnosis of the disorder. Diagnosis is sometimes challenging and can require use of imaging and nerve biopsy. Steroids and intravenous immunoglobulin are effective, and plasma exchange can be helpful as rescue therapy. The usefulness of immunosuppressants needs to be established. The identification of specific diagnostic markers and new therapeutic strategies with conventional or targeted immunotherapy are needed to improve the outlook for patients with CIDP. © 2010 Elsevier Ltd. All rights reserved.


Leonhardt S.D.,University of Wurzburg | Kaltenpoth M.,Max Planck Institute for Chemical Ecology
PLoS ONE | Year: 2014

Bacterial symbionts of insects have received increasing attention due to their prominent role in nutrient acquisition and defense. In social bees, symbiotic bacteria can maintain colony homeostasis and fitness, and the loss or alteration of the bacterial community may be associated with the ongoing bee decline observed worldwide. However, analyses of microbiota associated with bees have been largely confined to the social honeybees (Apis mellifera) and bumblebees (Bombus spec.), revealing - among other taxa - host-specific lactic acid bacteria (LAB, genus Lactobacillus) that are not found in solitary bees. Here, we characterized the microbiota of three Australian stingless bee species (Apidae: Meliponini) of two phylogenetically distant genera (Tetragonula and Austroplebeia). Besides common plant bacteria, we find LAB in all three species, showing that LAB are shared by honeybees, bumblebees and stingless bees across geographical regions. However, while LAB of the honeybee-associated Firm4-5 clusters were present in Tetragonula , they were lacking in Austroplebeia. Instead, we found a novel clade of likely host-specific LAB in all three Australian stingless bee species which forms a sister clade to a large cluster of Halictidae-associated lactobacilli. Our findings indicate both a phylogenetic and geographical signal of host-specific LAB in stingless bees and highlight stingless bees as an interesting group to investigate the evolutionary history of the bee-LAB association. © 2014 Leonhardt, Kaltenpoth.


Schleyer M.,University of Wurzburg
Learning & memory (Cold Spring Harbor, N.Y.) | Year: 2011

Drosophila larvae combine a numerically simple brain, a correspondingly moderate behavioral complexity, and the availability of a rich toolbox for transgenic manipulation. This makes them attractive as a study case when trying to achieve a circuit-level understanding of behavior organization. From a series of behavioral experiments, we suggest a circuitry of chemosensory processing, odor-tastant memory trace formation, and the "decision" process to behaviorally express these memory traces--or not. The model incorporates statements about the neuronal organization of innate vs. conditioned chemosensory behavior, and the types of interaction between olfactory and gustatory pathways during the establishment as well as the behavioral expression of odor-tastant memory traces. It in particular suggests that innate olfactory behavior is responsive in nature, whereas conditioned olfactory behavior is captured better when seen as an action in pursuit of its outcome. It incorporates the available neuroanatomical and behavioral data and thus should be useful as scaffold for the ongoing investigations of the chemo-behavioral system in larval Drosophila. © 2011 Cold Spring Harbor Laboratory Press


Herbert B.M.,University Hospital of Tuebingen | Muth E.R.,Clemson University | Pollatos O.,University of Potsdam | Herbert C.,University of Wurzburg
PLoS ONE | Year: 2012

The individual sensitivity for ones internal bodily signals ("interoceptive awareness") has been shown to be of relevance for a broad range of cognitive and affective functions. Interoceptive awareness has been primarily assessed via measuring the sensitivity for ones cardiac signals ("cardiac awareness") which can be non-invasively measured by heartbeat perception tasks. It is an open question whether cardiac awareness is related to the sensitivity for other bodily, visceral functions. This study investigated the relationship between cardiac awareness and the sensitivity for gastric functions in healthy female persons by using non-invasive methods. Heartbeat perception as a measure for cardiac awareness was assessed by a heartbeat tracking task and gastric sensitivity was assessed by a water load test. Gastric myoelectrical activity was measured by electrogastrography (EGG) and subjective feelings of fullness, valence, arousal and nausea were assessed. The results show that cardiac awareness was inversely correlated with ingested water volume and with normogastric activity after water load. However, persons with good and poor cardiac awareness did not differ in their subjective ratings of fullness, nausea and affective feelings after drinking. This suggests that good heartbeat perceivers ingested less water because they subjectively felt more intense signals of fullness during this lower amount of water intake compared to poor heartbeat perceivers who ingested more water until feeling the same signs of fullness. These findings demonstrate that cardiac awareness is related to greater sensitivity for gastric functions, suggesting that there is a general sensitivity for interoceptive processes across the gastric and cardiac modality. © 2012 Herbert et al.


Geiger D.,University of Wurzburg
Molecular Plant | Year: 2011

The majority of higher plants use sucrose as their main mobile carbohydrate. Proton-driven sucrose transporters play a crucial role in cell-to-cell and long-distance distribution of sucrose throughout the plant. A very negative plant membrane potential and the ability of sucrose transporters to accumulate sucrose concentrations of more than 1M indicate that plants evolved transporters with unique structural and functional features. The knowledge about the transport mechanism and structural/functional domains of these nano-machines is, however, still fragmentary. In this review, the current knowledge about the biophysical properties of plant sucrose transporters is summarized and discussed. © 2011 The Author.


Nollenburg M.,Karlsruhe Institute of Technology | Wolff A.,University of Wurzburg
IEEE Transactions on Visualization and Computer Graphics | Year: 2011

Metro maps are schematic diagrams of public transport networks that serve as visual aids for route planning and navigation tasks. It is a challenging problem in network visualization to automatically draw appealing metro maps. There are two aspects to this problem that depend on each other: the layout problem of finding station and link coordinates and the labeling problem of placing nonoverlapping station labels. In this paper, we present a new integral approach that solves the combined layout and labeling problem (each of which, independently, is known to be NP-hard) using mixed-integer programming (MIP). We identify seven design rules used in most real-world metro maps. We split these rules into hard and soft constraints and translate them into an MIP model. Our MIP formulation finds a metro map that satisfies all hard constraints (if such a drawing exists) and minimizes a weighted sum of costs that correspond to the soft constraints. We have implemented the MIP model and present a case study and the results of an expert assessment to evaluate the performance of our approach in comparison to both manually designed official maps and results of previous layout methods. © 2011 IEEE.


Crivellin A.,University of Bern | Hofer L.,University of Wurzburg | Rosiek J.,University of Warsaw
Journal of High Energy Physics | Year: 2011

In this article we present the complete resummation of the leading chirallyenhanced corrections stemming from gluino-squark, chargino-sfermion and neutralino-sfermion loops in the MSSM with non-minimal sources of flavor-violation. We compute the finite renormalization of fermion masses and the CKM matrix induced by chirality-flipping self-energies. In the decoupling limit MSUSY ≫ v, which is an excellent approximation to the full theory, we give analytic results for the effective gaugino(higgsino)-fermion- sfermion and the Higgs-fermion-fermion vertices. Using these vertices as effective Feynman rules, all leading chirally-enhanced corrections can consistently be included into perturbative calculations of Feynman amplitudes. We also give a generalized parametrization for the bare CKM matrix which extends the classic Wolfenstein parametrization to the case of complex parameters λ and A. © SISSA 2011.


Stolberg M.,University of Wurzburg
Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical Sciences | Year: 2012

Contrary to a widely held belief, the medicalization of obesity is not a recent development. Obesity was extensively discussed in leading early modern medical textbooks, as well as in dozens of seventeenth- and eighteenth-century dissertations. Drawing upon ancient and medieval writings, these works discussed the negative impact of obesity upon health and linked it with premature death. Obesity was particularly associated with apoplexy, paralysis, asthma and putrid fevers, and a range of therapeutic options was proposed. This paper offers a first survey of the medical understanding of the causes, effects and treatment of obesity in the early modern period. It examines the driving forces behind the physicians' interest and traces the apparently rather limited response to their claims among the general public. Comparing early modern accounts of obesity with the views and stereotypes prevailing today, it notes the impact of changing medical, moral and aesthetic considerations and identifies, among other things, a shift in the early modern period from concepts of pathological compression to images of the obese body as lax and boundless. © 2011 Elsevier Ltd.


Passarino G.,University of Turin | Passarino G.,National Institute of Nuclear Physics, Italy | Sturm C.,Max Planck Institute for Physics | Uccirati S.,University of Wurzburg
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

Complete electroweak two-loop corrections to the process gg→H are presented and discussed in a Standard Model with a fourth generation of heavy fermions. The latter is studied at the LHC to put exclusion limits on a fourth generation of heavy fermions. Therefore also a precise knowledge of the electroweak (EW) next-to-leading-order (NLO) corrections is important. The corrections due to the fourth generation are positive and large for a light Higgs boson, positive but relatively small around the t --t threshold and start to become negative for a Higgs boson mass around M H=450GeV. Increasing further the value of the Higgs boson mass, the EW NLO effects tend to become huge and negative, O(-100%), around the heavy-fermion threshold, assumed at 1.2TeV, so that gg-fusion becomes non-perturbative. Above that threshold they start to grow again and become positive around M H=1.75TeV. The behavior at even larger values of M H shows a positive enhancement, O(+100%) at M H=3TeV. © 2011 Elsevier B.V.


Schulze A.,University of Wurzburg
Nature Chemical Biology | Year: 2016

The Hsp90 chaperone is a central node of protein homeostasis, activating many diverse client proteins. Hsp90 functions as a molecular clamp that closes and opens in response to the binding and hydrolysis of ATP. Crystallographic studies have defined distinct conformational states of the mechanistic core, implying structural changes that have not yet been observed in solution. Here we engineered one-nanometer fluorescence probes based on photoinduced electron transfer into the yeast Hsp90 to observe these motions. We found that the ATPase activity of the chaperone was reflected in the kinetics of specific structural rearrangements at remote positions that acted cooperatively. Nanosecond single-molecule fluorescence fluctuation analysis uncovered that critical structural elements that undergo rearrangement were mobile on a sub-millisecond time scale. We identified a two-step mechanism for lid closure over the nucleotide-binding pocket. The activating co-chaperone Aha1 mobilized the lid of apo Hsp90, suggesting an early role in the catalytic cycle. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Meloni D.,University of Wurzburg | Morisi S.,University of Valencia | Peinado E.,University of Valencia
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

We present a model based on the A4 non-Abelian discrete symmetry leading to a predictive five-parameter neutrino mass matrix and providing a stable dark matter candidate. We found an interesting correlation among the atmospheric and the reactor angles which predicts Θ23∼Π/4 for very small reactor angle and deviation from maximal atmospheric mixing for large Θ13. Only normal neutrino mass spectrum is possible and the effective mass entering the neutrinoless double beta decay rate is constrained to be |mee|>4×10-4 eV. © 2011 Elsevier B.V.


OBJECTIVE:: To assess whether intracranial aneurysms are detectable with appropriate image quality with intraoperative 3-dimensional fluoroscopy with intravenous contrast administration.BACKGROUND:: Intraoperative imaging of cerebral aneurysms may be desirable in emergency situations with large space-occupying hematomas or to visualize vessels after clip placement. Mobile 3-dimensional fluoroscopes are available in a number of neurosurgical departments and may be useful in combination with simple image postprocessing to depict cerebral vessels.METHODS:: Eight patients were included in the study. The patientsʼ heads were fixed in a radiolucent Mayfield clamp. First, a rotational fluoroscopy scan was performed without contrast agent. Then, a second scan with 50 mL iodine contrast agent was performed. The DICOM (digital imaging and communications in medicine) data of both scans were transferred to an Apple PowerMac workstation, subtracted, and reconstructed with OsiriX imaging software. The images were compared with preoperative angiograms.RESULTS:: No adverse effects were observed during contrast administration. The entire procedure from fluoroscope positioning to the production of usable 3-dimensional images took 5 to 6 minutes with an image acquisition time of 2 × 24 seconds. The configuration of the aneurysm and the vessel anatomy were assessable. Previous coiling limited image quality in 1 patient.CONCLUSION:: This technique quickly provides images of adequate quality to assess the configuration of intracranial aneurysms, which may be helpful when immediate intraoperative information about intracranial vessel pathologies is required. The positioning of the fluoroscope, image acquisition, and processing can be completely integrated into the surgical workflow.ABBREVIATIONS:: Acom, anterior communicating arteryCTA, computed tomography angiographyDICOM, digital imaging and communications in medicineDSA, digital subtraction angiographyMCA, middle cerebral arteryMRA, magnetic resonance angiographySAH, subarachnoid hemorrhage Copyright © by the Congress of Neurological Surgeons


Christi M.,University of Wurzburg | Hopf H.,TU Braunschweig
Angewandte Chemie - International Edition | Year: 2010

(Figure Presented) Obscure mechanism: [12]Annulyne 1 and three of its isomers were reported in two recent publications as products from the reaction of potassium tert-butoxide (KOtBu) with 1,5-hexadiyne (2), although a plausible mechanism was not proposed. A careful examination of the NMR spectra has now proven that only the two possible 1, 3-hexadien-5-ynes (3) were produced. This result had already been obtained by Sondheimer et al. in 1961. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.


Fraunholz M.,University of Wurzburg
Frontiers in cellular and infection microbiology | Year: 2012

Staphylococcus aureus uses a plethora of virulence factors to accommodate a diversity of niches in its human host. Aside from the classical manifestations of S. aureus-induced diseases, the pathogen also invades and survives within mammalian host cells.The survival strategies of the pathogen are as diverse as strains or host cell types used. S. aureus is able to replicate in the phagosome or freely in the cytoplasm of its host cells. It escapes the phagosome of professional and non-professional phagocytes, subverts autophagy, induces cell death mechanisms such as apoptosis and pyronecrosis, and even can induce anti-apoptotic programs in phagocytes. The focus of this review is to present a guide to recent research outlining the variety of intracellular fates of S. aureus.


Chao Y.,Max Planck Institute for Infection Biology | Vogel J.,Max Planck Institute for Infection Biology | Vogel J.,University of Wurzburg
Current Opinion in Microbiology | Year: 2010

The ubiquitous RNA-binding protein, Hfq, has been shown to be required for the fitness and virulence of an increasing number of bacterial pathogens. Mutants lacking Hfq are often sensitive to host defense mechanisms and highly attenuated in animal models, albeit there is considerable variation in both severity and extent of phenotypes. RNomics and deep sequencing (RNA-seq) approaches discovered the small RNA and mRNA targets of Hfq, and indicated that this protein might impact on the expression of up to 20% of all genes in some organisms, including genes of type 3 secretion systems. Hfq also facilitates post-transcriptional cross-talk between the core and variable genome regions of bacterial pathogens, and might help integrate horizontally acquired virulence genes into existing regulatory networks. © 2010 Elsevier Ltd. All rights reserved.


Zernecke A.,University of Wurzburg | Zernecke A.,TU Munich | Zernecke A.,German Center for Cardiovascular Research | Weber C.,German Center for Cardiovascular Research | Weber C.,Ludwig Maximilians University of Munich
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2014

Chemokines play important roles in atherosclerotic vascular disease. Expressed by not only cells of the vessel wall but also emigrated leukocytes, chemokines were initially discovered to direct leukocytes to sites of inflammation. However, chemokines can also exert multiple functions beyond cell recruitment. Here, we discuss novel and recently emerging aspects of chemokines and their involvement in atherosclerosis. While reviewing newly identified roles of chemokines and their receptors in monocyte and neutrophil recruitment during atherogenesis and atheroregression, we also revisit homeostatic functions of chemokines, including their roles in cell homeostasis and foam cell formation. The functional diversity of chemokines in atherosclerosis warrants a clear-cut mechanistic dissection and stage-specific assessment to better appreciate the full scope of their actions in vascular inflammation and to identify pathways that harbor the potential for a therapeutic targeting of chemokines in atherosclerosis. © 2014 American Heart Association, Inc.


Nagorsen D.,Amgen | Kufer P.,Amgen | Baeuerle P.A.,Amgen | Bargou R.,University of Wurzburg
Pharmacology and Therapeutics | Year: 2012

For decades, chemotherapy has been the backbone for the treatment of patients with B cell malignancies. Depending on the individual disease, monoclonal antibodies, irradiation and/or hematopoietic stem cell transplantation are added. However, the current standard of care - particularly for patients with relapsed disease - is often not sufficient to achieve durable remissions. A highly promising new drug candidate in late-stage clinical development for treatment of B cell malignancies is blinatumomab (MT103 or AMG 103). This bispecific antibody construct has dual specificity for CD19 and CD3 and belongs to the class of bispecific T cell engager (BiTE®) antibodies, which can potentially engage all cytotoxic T cells of a patient for redirected lysis of tumor cells. Here, we review how blinatumomab has so far been pre-clinically and clinically developed for the treatment of patients with non-Hodgkin's lymphoma and acute lymphoblastic leukemia. © 2012 Elsevier Inc. All rights reserved.


Jimenez P.N.,Instituto Gulbenkian Of Ciencia | Jimenez P.N.,University of Groningen | Koch G.,University of Groningen | Koch G.,University of Wurzburg | And 5 more authors.
Microbiology and Molecular Biology Reviews | Year: 2012

Cell-to-cell communication is a major process that allows bacteria to sense and coordinately react to the fluctuating conditions of the surrounding environment. In several pathogens, this process triggers the production of virulence factors and/or a switch in bacterial lifestyle that is a major determining factor in the outcome and severity of the infection. Understanding how bacteria control these signaling systems is crucial to the development of novel antimicrobial agents capable of reducing virulence while allowing the immune system of the host to clear bacterial infection, an approach likely to reduce the selective pressures for development of resistance. We provide here an up-to-date overview of the molecular basis and physiological implications of cell-to-cell signaling systems in Gram-negative bacteria, focusing on the well-studied bacterium Pseudomonas aeruginosa. All of the known cell-to-cell signaling systems in this bacterium are described, from the most-studied systems, i.e., N-acyl homoserine lactones (AHLs), the 4-quinolones, the global activator of antibiotic and cyanide synthesis (GAC), the cyclic di-GMP (c-di-GMP) and cyclic AMP (cAMP) systems, and the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), to less-well-studied signaling molecules, including diketopiperazines, fatty acids (diffusible signal factor [DSF]-like factors), pyoverdine, and pyocyanin. This overview clearly illustrates that bacterial communication is far more complex than initially thought and delivers a clear distinction between signals that are quorum sensing dependent and those relying on alternative factors for their production. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Daghofer M.,Institute For Theoretische Festkorperphysik | Hohenadler M.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2014

We use exact diagonalization and cluster perturbation theory to address the role of strong interactions and quantum fluctuations for spinless fermions on the honeycomb lattice. We find quantum fluctuations to be very pronounced both at weak and strong interactions. A weak second-neighbor Coulomb repulsion V2 induces a tendency toward an interaction-generated quantum anomalous Hall phase, as borne out in mean-field theory. However, quantum fluctuations prevent the formation of a stable quantum Hall phase before the onset of the charge-modulated phase predicted at large V2 by mean-field theory. Consequently, the system undergoes a direct transition from the semimetal to the charge-modulated phase. For the latter, charge fluctuations also play a key role. While the phase, which is related to pinball liquids, is stabilized by the repulsion V2, the energy of its low-lying charge excitations scales with the electronic hopping t, as in a band insulator. © 2014 American Physical Society.


Fernandez Martinez E.,Max Planck Institute for Physics | Fernandez Martinez E.,CERN | Meloni D.,University of Wurzburg
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

We investigate how models for neutrino-nucleus cross sections based on different assumptions for the nuclear dynamics affect the forecasted sensitivities to neutrino oscillation parameters at future neutrino facilities. We limit ourselves to the quasi-elastic regime, where the neutrino cross sections can be evaluated with less uncertainties, and discuss the sensitivity reach to θ13 and δ at a prototype low-γ β-beam, mostly sensitive to the quasi-elastic regime. © 2011 Elsevier B.V.


Reuther J.,California Institute of Technology | Thomale R.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2014

Functional renormalization group (FRG) has become a diverse and powerful tool to derive effective low-energy scattering vertices of interacting many-body systems. Starting from a free expansion point of the action, the flow of the RG parameter Λ allows us to trace the evolution of the effective one- and two-particle vertices towards low energies by taking into account the vertex corrections between all parquet channels in an unbiased fashion. In this work, we generalize the expansion point at which the diagrammatic resummation procedure is initiated from a free UV limit to a cluster product state. We formulate a cluster FRG scheme where the noninteracting building blocks (i.e., decoupled spin clusters) are treated exactly, and the intercluster couplings are addressed via RG. As a benchmark study, we apply our cluster FRG scheme to the spin-12 bilayer Heisenberg model (BHM) on a square lattice where the neighboring sites in the two layers form the individual two-site clusters. Comparing with existing numerical evidence for the BHM, we obtain reasonable findings for the spin susceptibility, the spin-triplet excitation energy, and quasiparticle weight even in coupling regimes close to antiferromagnetic order. The concept of cluster FRG promises applications to a large class of interacting electron systems. © 2014 American Physical Society.


Buchberger A.,University of Wurzburg
Sub-Cellular Biochemistry | Year: 2010

Cdc48 (alias p97, VCP) is an important motor and regulator for the turnover of ubiquitylated proteins, both in proteasomal degradation and in nonproteolytic pathways. The diverse cellular tasks of Cdc48 are controlled by a large number of cofactors. Substrate-recruiting cofactors mediate the specific recognition of ubiquitylated target proteins, whereas substrate-processing cofactors often exhibit ubiquitin ligase or deubiquitylating activities that enable them to modulate the ubiquitylation state of substrates. This chapter introduces the major groups of Cdc48 cofactors and discusses the versatile options of substrate-processing cofactors to control the fate of Cdc48 substrates. © 2010 Landes Bioscience and Springer Science+Business Media


Schneider C.,University of Wurzburg
Nature Photonics | Year: 2016

Coherent control of individual two-level systems is at the heart of any quantum information protocol. In solids, two-level systems generated by bound electron–hole excitonic states, trapped in semiconductor quantum dots, display a robust coupling with light, enabling their optical manipulation via avant-garde approaches of nonlinear spectroscopy. Here, we develop a novel toolbox for coherent control of a quantum dot exciton based on the nonlinear wave-mixing responses, which are enhanced by a photonic nanostructure. By employing three, short, resonant laser pulses, we show that we can manipulate, at will, the intrinsic coherence of the quantum dot dipole and therefore engineer the spectro-temporal shape of its coherent emission. Multi-pulse quantum control sequences, which have been successful in NMR spectroscopy and quantum computation, can now be applied to optically active solid-state quantum bits with application in high-order nonlinear spectroscopy, ultrafast quantum optoelectronics and spread spectrum technology at the single emitter level. © 2016 Nature Publishing Group


Haigis W.,University of Wurzburg
Acta Clinica Croatica, Supplement | Year: 2012

In IOL formulas, the lens itself is represented by specific constants. Usually, these are given by the manufacturers as averages that need customization to allow for individual measurement setups. Apart from the instrumentation, patient characteristics such as axial length distribution may influence IOL constants, as demonstrated in this study. The effect of axial length on different IOL constants was studied on model calculations in theoretical ametropic eyes derived from the standard Gullstrand eye as well as in clinical results obtained for different surgical centers within the ULIB project in optical biometry. The model calculations showed definite dependence of IOL constants of different formulas on axial length, which was strongest for the SRK II A-constant. Clinical results are in good qualitative and quantitative agreement with SRK/T A-constants varying within 0.4 D for axial length averages of 23.2 to 24.2 mm. Even if the same instrumentation is used, different IOL constants may be necessary due to different axial length means in the respective patient populations. Thus, for best refractive results, constant individualization should be done at the surgeon level. Published constants like ULIB constants are nevertheless a good starting point.


Loock C.-M.,ETH Zurich | Staake T.,University of Bamberg | Thiesse F.,University of Wurzburg
MIS Quarterly: Management Information Systems | Year: 2013

This study investigates the role of information systems in stimulating energy-efficient behavior in private households. We present the example of Velix, a web portal designed to motivate customers of a utility company to reduce their electricity consumption. In particular, we consider the effectiveness of goal setting functionality and defaults in influencing energy conservation behavior. For this purpose, we use the web portal as a test of the theoretical propositions underlying its design. Based on data collected from a field experiment with 1,791 electricity consumers, we test hypotheses regarding the structural relations between defaults and goals, the impact of defaults and goals on consumption behavior, and the moderating role of feedback on goal choice. Our results confirm the positive impact of goal setting on energy conservation. We show that default goals lead to statistically significant savings by affecting goal choice. However, if the default goals are set too low or too high with respect to a self-set goal, the defaults will detrimentally affect behavior. We also show that feedback on goal attainment moderates the effect of default goals on goal choice. The results extend the knowledge on goal setting and defaults and have implications for the design of effective energy feedback systems. The study's approach, which combines hypothesis-driven work and design-oriented IS research, could serve as a blueprint for further research endeavors of this kind, particularly with regard to feedback systems based on future smart metering infrastructures.


Altmann M.,University of Wurzburg
International Journal of Production Research | Year: 2015

Sustainable business development is one of the main topics of research and management in recent years. Since the environmental pillar is a part of the sustainability concept, companies are forced to (re-)design their supply chain according to environmental issues. Both government and other stakeholders, e.g. non-governmental organisations and customers, pay a lot of attention on a companys environmental performance. Hence there is a risk of losing reputation if a company does not comply with environmental norms. We focus on the impact of customers requirements regarding the environmental performance of a product on strategic supply chain design decisions of the manufacturer of the product. Thus, we consider the case of a German manufacturing company and present a mixed-integer linear programming supply chain design model with a demand function that is influenced by sustainability requirements. The company is assumed to be able to improve the environmental performance of the products sold and affect the customer demand positively by designing an environmentally conscious supply chain. © 2014 Taylor & Francis.


Rendl S.,University of Wurzburg
Journal of musculoskeletal & neuronal interactions | Year: 2013

To evaluate the therapy decisive clinical risk factors (CRFs) in tools provided by WHO (WHO-FRAX) and the Head Osteology Organization of Germany (DVO) in a clinical setting, and, the degree of agreement between them. Three hundred subjects, 40 to 88 years of age, were consecutively referred for an evaluation of osteoporosis-related fracture risk, and therapy was possibly recommended. The evaluation used the 12 CRFs in the FRAX tool and the 21 CRFs in the DVO tool. We analyzed the degree of agreement and the strength of the CRFs in determining the therapy decision. RESULTs: Before evaluation, 52 (17.3%) of the patients took anti-osteoporotic medication. The FRAX tool indicated 36 (12.0%) patients suggested for treatment when hip density was included as a CRF, whereas the DVO tool indicated 80 (26.7%) and 91(30.3%), depending on bone density site. The pre- and post-test results agreed poorly to fair, whereas agreement was poor to good within both models and using the plain T-score to define the therapy intervention threshold. CRFs with debatable evidence reached significant influence on therapy decision. A considerably divergent number of patients were identified as treatment candidates, deserving further investigation to confirm the usefulness of some CRFs.


Colnot T.,CIS Toxicology | Kacew S.,University of Ottawa | Dekant W.,University of Wurzburg
Archives of Toxicology | Year: 2014

The compound 2,2′,6,6′-Tetrabromo-4,4′- isopropylidenediphenol (tetrabromobisphenol A, TBBPA) is used as a reactive and additive flame retardant. This review evaluates the mammalian toxicology of TBBPA and summarizes recent human exposure and risk assessments. TBBPA has a low potential for systemic or reproductive toxicity, and no-observed-adverse- effect-levels were greater than 1,000 mg/kg body weight (bw)/day in a 90-day oral toxicity study, a developmental toxicity study and a two-generation reproductive and developmental toxicity study. Some interactions of TBBPA with hormone-mediated pathways were noted in vitro; however, when studied in vivo, TBBPA did not produce adverse effects that might be considered to be related to disturbances in the endocrine system. Therefore, in accordance with internationally accepted definitions, TBBPA should not be considered an "endocrine disruptor." Furthermore, TBBPA is rapidly excreted in mammals and therefore does not have a potential for bioaccumulation. Measured concentrations of TBBPA in house dust, human diet and human serum samples are very low. Daily intakes of TBBPA in humans were estimated to not exceed a few ng/kg bw/day. Due to the low exposures and the low potential for toxicity, margins of exposures for TBBPA in the human population were between 6 × 104 (infants) to 6 × 107 (adults). Exposures of the general population are also well below the derived-no-effect-levels derived for endpoints of potential concern in REACH. © 2013 Springer-Verlag Berlin Heidelberg.


Evidence-based pharmacological treatment options for patients with persistent inguinal postherniorrhaphy pain are lacking. Twenty-one male patients, with severe, unilateral, persistent inguinal postherniorrhaphy pain, participated in a randomized, double-blind, placebo-controlled crossover trial, receiving lidocaine patch (5%) and placebo patch treatments in periods of 14 days separated by a 14-day wash-out period. Pain intensities (at rest, during movement, and pressure evoked [Numerical Rating Scale]) were assessed before treatment and on the last 3 days of each treatment period. Patients were a priori divided into two subgroups based on quantitative sensory testing (+/- thermal "hyposensitivity"). Skin biopsies for intraepidermal nerve fiber density assessment were taken at baseline, and quantitative sensory testing was performed before and after each treatment period. The primary outcome was change in pain intensity assessed as the difference in summed pain intensity differences between lidocaine and placebo patch treatments. There was no difference in summed pain intensity differences between lidocaine and placebo patch treatments in all patients (mean difference 6.2% [95% CI = -6.6 to 18.9%]; P = 0.33) or in the two subgroups (+/- thermal "hyposensitivity"). The quantitative sensory testing (n = 21) demonstrated an increased pressure pain thresholds after lidocaine compared with placebo patch treatment. Baseline intraepidermal nerve fiber density (n = 21) was lower on the pain side compared with the nonpain side (-3.8 fibers per millimeter [95% CI = -6.1 to -1.4]; P = 0.003). One patient developed mild erythema in the groin during both treatments. Lidocaine patch treatment did not reduce combined resting and dynamic pain ratings compared with placebo in patients with severe, persistent inguinal postherniorrhaphy pain.


Baumeister J.,University of Wurzburg
Knowledge-Based Systems | Year: 2011

In today's industrial applications, we see that knowledge systems are successfully implemented. However, critical domains require the elaborate and thoughtful validation of the knowledge bases before the deployment. Empirical testing, also known as regression testing, denotes the most popular validation technique, where predefined test cases are used to simulate and review the correct behavior of the system. In this paper, we motivate that the classic notions of a test case and the corresponding measures are not sufficient in many application scenarios. We present enhanced notions generalizing the standard test case, and we show appropriate extensions of the measures precision and recall, that work on these test case notions. Furthermore, the effective inspection of test runs is important whenever test cases fail. We introduce a novel visualization technique that allows for the effective and intuitive analysis of test cases and test run outcomes. The new visualization is useful for debugging a knowledge base and test case, respectively, but it also provides an intuitive overview of the status of the entire test suite. A case study reports on the (repeated) validation of a medical decision-support system and demonstrates the practical relevance of the presented work. © 2010 Elsevier B.V. All rights reserved.


Lehmann M.,University of Wurzburg
Topics in Current Chemistry | Year: 2012

The chapter introduces and defines the term star-shaped mesogens as a highly symmetric subgroup of multipodes. Hekates, the three arm stars, are in the focus of the other sections. Flexible, semi-flexible and shape-persistent mesogens can be distinguished. The chapter presents various modes of self-assembly which account for nanosegregation and space-filling. Recent examples are semi-flexible structures which fold to E-shaped conformers followed by self-organisation in columnar 2D and 3D and micellar cubic structures. Hekates are mesogens that will allow the design of complex mesomorphic and functional materials in the future. © 2011 Springer-Verlag Berlin Heidelberg.


Weiss C.H.,University of Wurzburg
Statistics and Computing | Year: 2011

Several procedures of sequential pattern analysis are designed to detect frequently occurring patterns in a single categorical time series (episode mining). Based on these frequent patterns, rules are generated and evaluated, for example, in terms of their confidence. The confidence value is commonly interpreted as an estimate of a conditional probability, so some kind of stochastic model has to be assumed. The model is identified as a variable length Markov model. With this assumption, the usual confidences are maximum likelihood estimates of the transition probabilities of the Markov model. We discuss possibilities of how to efficiently fit an appropriate model to the data. Based on this model, rules are formulated. It is demonstrated that this new approach generates noticeably less and more reliable rules. © 2009 Springer Science+Business Media, LLC.


Burek M.,Institute of Anatomy and Cell Biology | Arias-Loza P.A.,University of Wurzburg | Forster C.Y.,Institute of Anatomy and Cell Biology
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

OBJECTIVE-: Estrogens have multiple effects on vascular physiology and function. In the present study, we look for direct estrogen target genes within junctional proteins. METHODS AND RESULTS-: We use murine endothelial cell lines of brain and heart origin, which express both subtypes of estrogen receptor, ERα and ERβ. Treatment of these cells with 17β-estradiol (E2) led to an increase in transendothelial electric resistance and a most prominent upregulation of the tight junction protein claudin-5 expression. A significant increase of claudin-5 promoter activity, mRNA, and protein levels was detected in cells from both vascular beds. In protein lysates and in immunoreactions on brain sections from ovariectomized E2-treated mice, we noticed an increase in claudin-5 protein and mRNA content. Treatment of cells with a specific ERβ agonist, diarylpropionitrile, revealed the same effect as E2 stimulation. Moreover, we detected significantly lower claudin-5 mRNA and protein content in ERβ knockout mice. CONCLUSIONS-: We describe claudin-5 as a novel estrogen target in vascular endothelium and show in vivo (brain endothelium) and in vitro (brain and heart endothelium) effects of estrogen on claudin-5 levels. The estrogen-induced increase in junctional protein levels may lead to an improvement in vascular structural integrity and barrier function of vascular endothelium. © 2010 American Heart Association, Inc.


Salkovic-Petrisic M.,University of Zagreb | Knezovic A.,University of Zagreb | Hoyer S.,University of Heidelberg | Riederer P.,University of Wurzburg
Journal of Neural Transmission | Year: 2013

Experimental models that faithfully mimic the developmental pathology of sporadic Alzheimer's disease (sAD) in humans are important for testing the novel therapeutic approaches in sAD treatment. Widely used transgenic mice AD models have provided valuable insights into the molecular mechanisms underlying the memory decline but, due to the particular β-amyloid-related gene manipulation, they resemble the familial but not the sporadic AD form, and are, therefore, inappropriate for this purpose. In line with the recent findings of sAD being recognised as an insulin resistant brains state (IRBS), a new, non-transgenic, animal model has been proposed as a representative model of sAD, developed by intracerebroventricular application of the betacytotoxic drug streptozotocin (STZ-icv). The STZ-icv-treated animals (mostly rats and mice) develop IRBS associated with memory impairment and progressive cholinergic deficits, glucose hypometabolism, oxidative stress and neurodegeneration that share many features in common with sAD in humans. The therapeutic strategies (acetylcholinesterase inhibitors, antioxidants and many other drugs) that have been tested until now on the STZ-icv animal model have been reviewed and the comparability of the drugs' efficacy in this non-transgenic sAD model and the results from clinical trials on sAD patients, evaluated. © 2012 Springer-Verlag.


Staub F.,University of Wurzburg
Computer Physics Communications | Year: 2011

SARAH is a Mathematica package for studying supersymmetric models. It calculates for a given model the masses, tadpole equations and all vertices at tree-level. This information can be used by SARAH to write model files for CalcHep/CompHep or FeynArts/FormCalc. In addition, the second version of SARAH can derive the renormalization group equations for the gauge couplings, parameters of the superpotential and soft-breaking parameters at one- and two-loop level. Furthermore, it calculates the one-loop self-energies and the one-loop corrections to the tadpoles. SARAH can handle all N=1 SUSY models whose gauge sector is a direct product of SU(N) and U(1) gauge groups. The particle content of the model can be an arbitrary number of chiral superfields transforming as any irreducible representation with respect to the gauge groups. To implement a new model, the user has just to define the gauge sector, the particle, the superpotential and the field rotations to mass eigenstates. © 2010 Elsevier B.V. All rights reserved.


Herzog M.,Max Planck Institute for Astrophysics | Ropke F.K.,University of Wurzburg
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2011

We present three-dimensional numerical simulations of turbulent combustion converting a neutron star into a quark star. Hadronic matter, described by a microphysical finite-temperature equation of state, is converted into strange quark matter. We assume this phase, represented by a bag-model equation of state, to be absolutely stable. Following the example of thermonuclear burning in white dwarfs leading to type Ia supernovae, we treat the conversion process as a potentially turbulent deflagration. Solving the nonrelativistic Euler equations using established numerical methods we conduct large eddy simulations including an elaborate subgrid scale model, while the propagation of the conversion front is modeled with a level-set method. Our results show that for large parts of the parameter space the conversion becomes turbulent and therefore significantly faster than in the laminar case. Despite assuming absolutely stable strange quark matter, in our hydrodynamic approximation an outer layer remains in the hadronic phase, because the conversion front stops when it reaches conditions under which the combustion is no longer exothermic. © 2011 American Physical Society.


Buchberger A.,University of Wurzburg
Sub-cellular biochemistry | Year: 2013

The chaperone-related, ubiquitin-selective AAA (ATPase associated with a variety of cellular activities) protein Cdc48 (also known as TER94, p97 and VCP) is a key regulator of intracellular proteolysis in eukaryotes. It uses the energy derived from ATP hydrolysis to segregate ubiquitylated proteins from stable assemblies with proteins, membranes and chromatin. Originally characterized as essential factor in proteasomal degradation pathways, Cdc48 was recently found to control lysosomal protein degradation as well. Moreover, impaired lysosomal proteolysis due to mutational inactivation of Cdc48 causes protein aggregation diseases in humans. This review introduces the major systems of intracellular proteolysis in eukaryotes and the role of protein ubiquitylation. It then discusses in detail structure, mechanism and cellular functions of Cdc48 with an emphasis on protein degradation pathways in yeast.


Schoor C.,TU Dresden | Bannert M.,University of Wurzburg
Computers in Human Behavior | Year: 2012

The purpose of this study was to explore sequences of social regulatory processes during a computer-supported collaborative learning task and their relationship to group performance. Analogous to self-regulation during individual learning, we conceptualized social regulation both as individual and as collaborative activities of analyzing, planning, monitoring and evaluating cognitive and motivational aspects during collaborative learning. We analyzed the data of 42 participants working together in dyads. They had 90 min to develop a common handout on a statistical topic while communicating only via chat and common editor. The log files of chat and editor were coded regarding activities of social regulation. Results show that participants in dyads with higher group performance (N = 20) did not differ from participants with lower group performance (N = 22) in the frequencies of regulatory activities. In an exploratory way, we used process mining to identify process patterns for high versus low group performance dyads. The resulting models show clear parallels between high and low achieving dyads in a double loop of working on the task, monitoring, and coordinating. Moreover, there are no major differences in the process of high versus low achieving dyads. Both results are discussed with regard to theoretical and empirical issues. Furthermore, the method of process mining is discussed. © 2012 Elsevier Ltd. All rights reserved.


Arbustini E.,Center for Inherited Cardiovascular Disease | Weidemann F.,University of Wurzburg | Hall J.L.,University of Minnesota
Journal of the American College of Cardiology | Year: 2014

Whether left ventricular noncompaction (LVNC) is a distinct cardiomyopathy or a morphologic trait shared by different cardiomyopathies remains controversial. Current guidelines from professional organizations recommend different strategies for diagnosing and treating patients with LVNC. This state-of-the-Art review discusses new insights into the basic mechanisms leading to LVNC, its clinical manifestations, treatment modalities, anatomy and pathology, embryology, genetics, epidemiology, and imaging. Three markers currently define LVNC: prominent left ventricular trabeculae, deep intertrabecular recesses, and a thin compacted layer. Although new genetic data from mice and humans supports LVNC as a distinct cardiomyopathy, evidence for LVNC as a shared morphological trait is not ruled out. Criteria supporting LVNC as a shared morphological trait may depend on consensus guidelines from the multiple professional organizations. Enhanced imaging and increased use of genetics are both predicted to significantly impact our overall understanding of the basic mechanisms causing LVNC and its optimal management. © 2014 American College of Cardiology Foundation.


Thomas W.,Mutterhaus der Borromaeerinnen | Speer C.P.,University of Wurzburg
Paediatric Respiratory Reviews | Year: 2014

Bronchopulmonary dysplasia (BPD) is a major sequel of extremely premature birth. Multiple ante- and postnatal factors act in concert to injure the immature lung in the pathogenesis of the disease. Among them, chorioamnionitis - according to current evidence - plays a pivotal role. Pulmonary inflammatory processes seen in animal models of chorioamnionitis resemble those seen in premature infants who developed BPD. Chorioamnionitis can doubtlessly induce extremely preterm birth, thus contributing to a gestation-dependent risk of BPD. A gestation-independent association of chorioamnionitis with an increased risk of developing BPD has been demonstrated by a recent systematic review of clinical observational studies. Antenatal inflammation with signs of a systemic fetal response reduces the response to exogenous surfactant in infants with respiratory distress syndrome, leading to a longer need for mechanical ventilation. Moreover, chorioamnionitis increases the risk of early onset sepsis. Both mechanical ventilation and sepsis are, however, major postnatal risk factors for BPD. © 2013 Elsevier Ltd.


Speer C.P.,University of Wurzburg | Sweet D.G.,Regional Neonatal Unit | Halliday H.L.,Regional Neonatal Unit
Early Human Development | Year: 2013

Surfactant replacement in preterm infants with respiratory distress syndrome (RDS) has been a major therapeutic breakthrough and the most intensively studied intervention in neonatal medicine. Surfactant whether given prophylactically in the delivery room or in babies with established RDS reduces the severity of RDS, the incidence of air leaks and pneumothorax and, most importantly, neonatal death. Many randomized controlled trials have explored different strategies to optimize the effect of surfactant administration and have further improved neonatal outcome. Whenever indicated, surfactant should be administered as early as possible in the course of the RDS. © 2013 Elsevier Ireland Ltd.


Hejna P.,Charles University | Bohnert M.,University of Wurzburg
Journal of Forensic Sciences | Year: 2013

Complete or incomplete decapitation as a consequence of suicidal hanging is very rare, few cases having been reported in the worldwide literature. Posthanging decapitation is typically related to a drop of several meters. Three cases of complete decapitation and one case of incomplete decapitation by suicidal hanging are reported with particular emphasis on internal findings and vital reaction patterns. Personal, circumstantial, autopsy, and toxicological data were analyzed to define basic characteristics of such extreme injuries. The crucial factor for the state of decapitation itself is the kinetic energy of the falling body, the strength of the human neck tissue, and the diameter and elasticity of the used ligature. Results of our case study suggest Simon's hemorrhage and air embolism as useful autopsy findings in posthanging beheading cases. Simon's hemorrhage was demonstrated in three cases of four. The test for air embolism was positive in all four cases. © 2012 American Academy of Forensic Sciences.


Topolinski S.,University of Wurzburg | Pereira P.T.,Schloss Werneck Hospital
Perception | Year: 2012

We investigated the impact of food deprivation on oral and manual haptic size perception of food and non-food objects. From relevant theories (need-proportional perception, motivated perception, frustrative nonreward, perceptual defence, and sensory sensitisation) at least four completely different competing predictions can be derived. Testing these predictions, we found across four experiments that participants estimated the length of both non-food and food objects to be larger when hungry than when satiated, which was true only for oral haptic perception, while manual haptic perception was not influenced by hunger state. Subjectively reported hunger correlated positively with estimated object size in oral, but not in manual, haptic perception. The impact of food deprivation on oral perception vanished after oral stimulations even for hungry individuals. These results favour a sensory sensitisation account maintaining that hunger itself does not alter oral perception but the accompanying lack of sensory stimulation of the oral mucosa. Both oral and manual haptic perception tended to underestimate actual object size. Finally, an enhancing effect of domain-target matching was found, ie food objects were perceived larger by oral than by manual haptics, while non-food objects were perceived larger by manual than by oral haptics. © 2012 a Pion publication.


Hot topics in polymer science in the recent years and decades included macromolecular engineering enabled by controlled and living polymerization, use of polymers in biomedical applications. Control over polymerization and the structure of polymers increased tremendously. Despite the increased control over various polymerization techniques, polymers are intrinsically statistical in nature leading to a structural variability. As researchers combine polymers and biological systems, we combine two complex systems. Interestingly though, only the study of biological assays is subject to systematic scrutiny with respect to their reproducibility and variability. Here, it is argued that polymer synthesis should also be considered with systematic variability analysis, in particular in connection with downstream processes such as biological assays. © 2015 Future Medicine Ltd.


Hartleb H.,Institute of Physical and Theoretical Chemistry | Spath F.,Institute of Physical and Theoretical Chemistry | Hertel T.,Institute of Physical and Theoretical Chemistry | Hertel T.,University of Wurzburg
ACS Nano | Year: 2015

We have investigated the photophysical properties of electrochemically gate-doped semiconducting single-wall carbon nanotubes (s-SWNTs). A comparison of photoluminescence (PL) and simultaneously recorded absorption spectra reveals that free-carrier densities correlate well with the first sub-band exciton or trion oscillator strengths but not with PL intensities. We thus used a global analysis of the first sub-band exciton absorption for a detailed investigation of gate-doping, here of the (6,5) SWNT valence band. Our data are consistent with a doping-induced valence band shift according to ΔÏμv = n × b, where n is the free-carrier density, Ïμv is the valence band edge, and b = 0.15 ± 0.05 eV·nm. We also predict such band gap renormalization of one-dimensional gate-doped semiconductors to be accompanied by a stepwise increase of the carrier density by Δn = (32meffb)/(πh)2 (meff is effective carrier mass). Moreover, we show that the width of the spectroelectrochemical window of the first sub-band exciton of 1.55 ± 0.05 eV corresponds to the fundamental band gap of the undoped (6,5) SWNTs in our samples and not to the renormalized band gap of the doped system. These observations as well as a previously unidentified absorption band emerging at high doping levels in the Pauli-blocked region of the single-particle Hartree band structure provide clear evidence for strong electronic correlations in the optical spectra of SWNTs. © 2015 American Chemical Society.


Fischbach W.,University of Wurzburg
Gastroenterology Clinics of North America | Year: 2013

Gastric marginal zone B-cell lymphoma of mucosal-associated lymphoid tissue (MALT) is the predominant entity within the primary gastrointestinal lymphomas. Helicobacter pylori represents the decisive pathogenetic factor for gastric MALT lymphoma. The goal of treating gastric MALT lymphoma should be complete cure. The first choice of treatment is H pylori eradication. Patients with histologically persistent residual lymphoma after successful H pylori eradication and normalization of endoscopic findings should be managed by a watch-and-wait strategy. Patients who do not respond to H pylori eradication should be referred for radiation or chemotherapy. © 2013 Elsevier Inc.


Grothe M.,University of Rostock | Heinsen H.,University of Wurzburg | Teipel S.,University of Rostock | Teipel S.,German Center for Neurodegenerative Diseases
Neurobiology of Aging | Year: 2013

Recent evidence from cross-sectional in vivo imaging studies suggests that atrophy of the cholinergic basal forebrain (BF) in Alzheimer's disease (AD) can be distinguished from normal age-related degeneration even at predementia stages of the disease. Longitudinal study designs are needed to specify the dynamics of BF degeneration in the transition from normal aging to AD. We applied recently developed techniques for in vivo volumetry of the BF to serial magnetic resonance imaging scans of 82 initially healthy elderly individuals (60-93 years) and 50 patients with very mild AD (Clinical Dementia Rating score = 0.5) that were clinically followed over an average of 3 ± 1.5 years. BF atrophy rates were found to be significantly higher than rates of global brain shrinkage even in cognitively stable healthy elderly individuals. Compared with healthy control subjects, very mild AD patients showed reduced BF volumes at baseline and increased volume loss over time. Atrophy of the BF was more pronounced in progressive patients compared with those that remained stable. The cholinergic BF undergoes disproportionate degeneration in the aging process, which is further increased by the presence of AD. © 2013 Elsevier Inc.


Conspectusπ-Conjugation between heterocyclic donor (D) and acceptor (A) groups via a polymethine chain leads to dyes with dipole moments greater than 10 D. These dipole moments direct the self-assembly of the dyes into antiparallel dimer aggregates, even in dilute solution, with binding strengths that are far beyond those observed for other π-scaffolds whose self-assembly is driven primarily by dispersion forces. The combination of directionality and exceptional binding strength of dipolar interactions between D-π-A dyes indeed resembles the situation of the hydrogen bond. Thus, similar to the latter, dipolar interactions between merocyanine dyes, a unique class of D-π-A chromophores, can be utilized to construct sophisticated supramolecular architectures of predictable geometry, particularly in low polarity environments.For bis(merocyanine) dyes it has been demonstrated that the self-assembly pathway is encoded in the tether between the two constituent merocyanine chromophores. If the tether enables the antiparallel stacking of the two appended dyes, folding takes place, which may be followed by further self-assembly into extended H-aggregate π-stacks at higher concentrations in solvents of low polarity. For tethers that do not support folding, the formation of bimolecular complexes of four merocyanine units, cyclic oligomers, and supramolecular polymers has been observed. For the former case, that is, formation of a bimolecular stack of four merocyanine units from tweezer-type molecules, association constants >109 M-1 were measured in chloroform. On the other hand, because only one π-face is utilized in the formation of supramolecular polymers from bis(merocyanine) dyes, higher hierarchical structures typically originate in which the other π-face is surrounded by an antiparallel π-stacked neighbor molecule.Among the observed self-assembled structures, nanorods in particular have attracted considerable attention because their self-assembly into well-defined H-aggregates falls under kinetic control and is slowed tremendously with decreasing solvent polarity. Co-assembly of achiral and chiral merocyanine building blocks or two enantiomers of a chiral merocyanine in different ratios provided insight into majority rules and sergeant-and-soldiers effects as well as the autocatalytic fiber growth process.With regard to materials applications, it is important to note that the high propensity for dipolar aggregation was disadvantageous for many envisioned applications of these dyes in the area of nonlinear optics. However, this aggregation behavior proved to be advantageous for the recently demonstrated applications of D-π-A dyes, in particular, merocyanines as p-type organic semiconductors in organic electronics and photovoltaics. Thus, organic transistors with hole mobilities >0.5 cm2/(V s) and organic solar cells with power conversion efficiencies >6% could be achieved with merocyanine-based organic semiconductor molecules. © 2016 American Chemical Society.


Thierschmann H.,University of Wurzburg
Nature Nanotechnology | Year: 2015

Rectification of thermal fluctuations in mesoscopic conductors is the key idea behind recent attempts to build nanoscale thermoelectric energy harvesters to convert heat into useful electric power. So far, most concepts have made use of the Seebeck effect in a two-terminal geometry, where heat and charge are both carried by the same particles. Here, we experimentally demonstrate the working principle of a new kind of energy harvester, proposed recently, using two capacitively coupled quantum dots. We show that, due to the novel three-terminal design of our device, which spatially separates the heat reservoir from the conductor circuit, the directions of charge and heat flow become decoupled. This enables us to manipulate the direction of the generated charge current by means of external gate voltages while leaving the direction of heat flow unaffected. Our results pave the way for a new generation of multi-terminal nanoscale heat engines. © 2015 Nature Publishing Group


Hofmann U.,University of Wurzburg | Frantz S.,Universitatsklinik Und Poliklinik For Innere Medizin Iii
Circulation Research | Year: 2015

A large body of evidence produced during decades of research indicates that myocardial injury activates innate immunity. On the one hand, innate immunity both aggravates ischemic injury and impedes remodeling after myocardial infarction (MI). On the other hand, innate immunity activation contributes to myocardial healing, as exemplified by monocytes' central role in the formation of a stable scar and protection against intraventricular thrombi after acute infarction. Although innate leukocytes can recognize a wide array of self-antigens via pattern recognition receptors, adaptive immunity activation requires highly specific cooperation between antigen-presenting cells and distinct antigen-specific receptors on lymphocytes. We have only recently begun to examine lymphocyte activation's relationship to adaptive immunity and significance in the context of ischemic myocardial injury. There is some experimental evidence that CD4+ T-cells contribute to ischemia-reperfusion injury. Several studies have shown that CD4+ T-cells, especially CD4+ T-regulatory cells, improve wound healing after MI, whereas depleting B-cells is beneficial post MI. That T-cell activation after MI is induced by T-cell receptor signaling implicates autoantigens that have not yet been identified in this context. Also, the significance of lymphocytes in humans post MI remains unclear, primarily as a result of methodology. This review summarizes current experimental evidence of lymphocytes' activation, functional role, and crosstalk with innate leukocytes in myocardial ischemia-reperfusion injury, wound healing, and remodeling after myocardial infarction. © 2014 American Heart Association, Inc.


Tonelli M.,University of Alberta | Wanner C.,University of Wurzburg
Annals of Internal Medicine | Year: 2014

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed a clinical practice guideline in 2013 on lipid management and treatment of all adults and children with chronic kidney disease (CKD). All forms of CKD are included (non-dialysis-dependent, dialysis-dependent, and kidney transplant recipients). Methods: The KDIGO Lipid Guideline Development Work Group defined the scope of the guideline, gathered evidence, determined topics for systematic review, and graded the quality of evidence that had been summarized by an evidence review team. Searches of the English-language literature were conducted through August 2011 and supplemented by targeted searches through June 2013. Final modification of the guidelines was informed by the KDIGO Board of Directors and a public review process involving registered stakeholders. Recommendations: The full guideline includes 13 recommendations; a key element was the recommendation for statin or statin with ezetimibe treatment of adults aged 50 years or older with estimated glomerular filtration rates less than 60 mL/min/1.73 m2 but not treated with long-term dialysis or kidney transplantation. This synopsis focuses on 8 recommendations pertinent to assessment of lipid status and treatment with a statin-based regimen in adults. © 2014 American College of Physicians.


Hebestreit H.,University of Wurzburg
European Respiratory Monograph | Year: 2014

Physical activity and exercise have become part of standard treatment in many centres caring for people with cystic fibrosis (CF). Observed benefits include positive effects on exercise capacity, pulmonary disease and health-related quality of life (HRQoL). Furthermore, some data also suggest improvements in bone mineral density and psychological well-being. However, exercise may carry some risks in CF. Most of the adverse events associated with exercise are more common in individuals with advanced disease. In addition to knowing a patient's medical history and actual health status, standardised cardiopulmonary exercise testing can identify patients at risk for many of the potential complications, as well as the reasons for a reduced exercise capacity. The Godfrey protocol for cycle ergometry is employed by many international experts. A proper individual risk assessment, as well as patient education and counselling, will foster an active and healthy lifestyle.


Haunert J.-H.,University of Wurzburg
ISPRS Journal of Photogrammetry and Remote Sensing | Year: 2012

This article presents an algorithmic approach to the problem of finding symmetries in building footprints, which is motivated by map generalization tasks such as symmetry-preserving building simplification and symmetry-aware grouping and aggregation. Moreover, symmetries in building footprints may be used for landmark selection and building classification. The presented method builds up on existing methods for symmetry detection in vector data that use algorithms for string matching. It detects both mirror symmetries and repetitions of geometric structures. In addition to the existing vector-based methods, the new method finds partial symmetries in polygons while allowing for small geometric errors and, based on a least-squares approach, computes optimally adjusted mirror axes and assesses their quality. Finally, the problem of grouping symmetry relations is addressed with an algorithm that finds mirror axes that are almost collinear. The presented approach was tested on a large building dataset of the metropolitan Boston area and its results were compared with results that were manually generated in an empirical test. The symmetry relations that the participants of the test considered most important were found by the algorithm. Future work will deal with the integration of information on symmetry relations into algorithms for map generalization. © 2012 International Society for Photogrammetry and Remote Sensing, Inc. (ISPRS).


Hohenadler M.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2013

Electron-phonon coupling plays a central role for time-dependent phenomena in condensed matter, for example, in photoexcitation experiments. We use the continuous-time quantum Monte Carlo method to study the real-time evolution of charge and spin correlation functions of a Peierls insulator after a quench to a noninteracting Hamiltonian. This approach gives exact results, and fully takes into account quantum phonon effects without relying on a Hilbert space truncation. It is also free from a dynamical sign problem. The observed time dependence is compared to free-fermion time evolution starting from a dimerized state. Our exact results provide a benchmark for more realistic calculations and may be directly applicable to experiments with cold atoms or trapped ions. © 2013 American Physical Society.


De Persis C.,University of Groningen | De Persis C.,University of Rome La Sapienza | Sailer R.,University of Wurzburg | Wirth F.,University of Rome La Sapienza
Automatica | Year: 2013

Consider the problem of stabilizing large-scale systems by distributed controllers, where the controllers exchange information via a shared limited communication medium. Event-triggered sampling schemes are proposed, in which each system decides when to transmit new information across the network based on the crossing of some error thresholds, which only depend on information locally available at individual subsystems. Stability of the interconnected large-scale system is inferred by applying a generalized small-gain theorem. © 2013 Published by Elsevier Ltd.


Pakmor R.,Heidelberger Institute For Theoretische Studien | Kromer M.,Max Planck Institute for Astrophysics | Taubenberger S.,Max Planck Institute for Astrophysics | Ropke F.K.,University of Wurzburg | Hillebrandt W.,Max Planck Institute for Astrophysics
Astrophysical Journal Letters | Year: 2012

One of the most important questions regarding the progenitor systems of Type Ia supernovae (SNe Ia) is whether mergers of two white dwarfs can lead to explosions that reproduce observations of normal events. Here we present a fully three-dimensional simulation of a violent merger of two carbon-oxygen white dwarfs with masses of 0.9 M ⊙ and 1.1 M ⊙ combining very high resolution and exact initial conditions. A well-tested combination of codes is used to study the system. We start with the dynamical inspiral phase and follow the subsequent thermonuclear explosion under the plausible assumption that a detonation forms in the process of merging. We then perform detailed nucleosynthesis calculations and radiative transfer simulations to predict synthetic observables from the homologously expanding supernova ejecta. We find that synthetic color light curves of our merger, which produces about 0.62 M ⊙ of 56Ni, show good agreement with those observed for normal SNe Ia in all wave bands from U to K. Line velocities in synthetic spectra around maximum light also agree well with observations. We conclude that violent mergers of massive white dwarfs can closely resemble normal SNe Ia. Therefore, depending on the number of such massive systems available these mergers may contribute at least a small fraction to the observed population of normal SNe Ia. © 2012 The American Astronomical Society. All rights reserved.


Muranyi W.,University of Heidelberg | Malkusch S.,University of Wurzburg | Muller B.,University of Heidelberg | Heilemann M.,Goethe University Frankfurt | And 2 more authors.
PLoS Pathogens | Year: 2013

The inner structural Gag proteins and the envelope (Env) glycoproteins of human immunodeficiency virus (HIV-1) traffic independently to the plasma membrane, where they assemble the nascent virion. HIV-1 carries a relatively low number of glycoproteins in its membrane, and the mechanism of Env recruitment and virus incorporation is incompletely understood. We employed dual-color super-resolution microscopy visualizing Gag assembly sites and HIV-1 Env proteins in virus-producing and in Env expressing cells. Distinctive HIV-1 Gag assembly sites were readily detected and were associated with Env clusters that always extended beyond the actual Gag assembly site and often showed enrichment at the periphery and surrounding the assembly site. Formation of these Env clusters depended on the presence of other HIV-1 proteins and on the long cytoplasmic tail (CT) of Env. CT deletion, a matrix mutation affecting Env incorporation or Env expression in the absence of other HIV-1 proteins led to much smaller Env clusters, which were not enriched at viral assembly sites. These results show that Env is recruited to HIV-1 assembly sites in a CT-dependent manner, while Env(ΔCT) appears to be randomly incorporated. The observed Env accumulation surrounding Gag assemblies, with a lower density on the actual bud, could facilitate viral spread in vivo. Keeping Env molecules on the nascent virus low may be important for escape from the humoral immune response, while cell-cell contacts mediated by surrounding Env molecules could promote HIV-1 transmission through the virological synapse. © 2013 Muranyi et al.


Sauer S.,Max Planck Institute for Molecular Genetics | Sauer S.,University of Wurzburg
Trends in Pharmacological Sciences | Year: 2015

Nuclear receptors are ligand-activated transcription factors, which represent a primary class of drug targets. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a key player in various biological processes. PPARγ is widely known as the target protein of the thiazolidinediones for treating type 2 diabetes. Moreover, PPARγ ligands can induce anti-inflammatory and potentially additional beneficial effects. Recent mechanistic insights of PPARγ modulation give hope the next generation of efficient PPARγ-based drugs with fewer side effects can be developed. Furthermore, chemical approaches that make use of synergistic action of combinatorial ligands are promising alternatives for providing tailored medicine. Lessons learned from fine-tuning the action of PPARγ can provide avenues for efficient molecular intervention via many other nuclear receptors to combat common diseases. © 2015 Elsevier Ltd. All rights reserved.


Dekant W.,University of Wurzburg | Colnot T.,CIS Toxicology
Toxicology Letters | Year: 2013

Hazard and risk assessment of chemicals with endocrine activity is hotly debated due to claimed non-monotonous dose-response curves in the low-dose region. In hazard identification a clear definition of "endocrine disruptors" (EDs) is required; this should be based on the WHO/IPCS definition of EDs and on adverse effects demonstrated in intact animals or humans. Therefore, endocrine effects are a mode of action potentially resulting in adverse effects; any classification should not be based on a mode of action, but on adverse effects. In addition, when relying on adverse effects, most effects reported in the low-dose region will not qualify for hazard identification since most have little relation to an adverse effect. Non-monotonous dose-response curves that had been postulated from limited, exploratory studies could also not be reproduced in targeted studies with elaborate quality assurance. Therefore, regulatory agencies or advisory bodies continue to apply the safety-factor method or the concept of "margin-of-exposure" based on no observed adverse effect levels (NOAELs) in the risk assessment of chemicals with weak hormonal activity. Consistent with this approach, tolerable levels regarding human exposure have been defined for such chemicals. To conclusively support non-monotonous dose-response curves, targeted experiments with a sufficient number of animals, determination of adverse endpoints, adequate statistics and quality control would be required. © 2013 Elsevier Ireland Ltd.


Mally A.,University of Wurzburg
Toxicological Sciences | Year: 2012

The mycotoxin and food contaminant ochratoxin A (OTA) is a potent renal carcinogen in rodents, but its mode of action (MoA) is still poorly defined. In 2006, the European Food Safety Authority concluded that there is a "lack of evidence for the existence of OTA-DNA adducts" and thus insufficient evidence to establish DNA reactivity as a MoA for tumor formation by OTA. In reviewing the available database on OTA toxicity, a MoA for renal carcinogenicity of OTA is developed that involves a combination of genetic instability and increased proliferative drive as consequences of OTA-mediated disruption of mitosis, whereby the organ- and site-specificity of tumor formation by OTA is determined by selective renal uptake of OTA into the proximal tubule epithelium. The proposed MoA is critically assessed with respect to concordance of dose-response of the suggested key events and tumor formation, their temporal association, consistency, and biological plausibility. Uncertainties, data gaps and needs for further research are highlighted. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Facchinei F.,University of Rome La Sapienza | Kanzow C.,University of Wurzburg
SIAM Journal on Optimization | Year: 2010

The generalized Nash equilibrium problem (GNEP) is an extension of the classical Nash equilibrium problem where both the objective functions and the constraints of each player may depend on the rivals' strategies. This class of problems has a multitude of important engineering applications, and yet solution algorithms are extremely scarce. In this paper, we analyze in detail a globally convergent penalty method that has favorable theoretical properties. We also consider strengthened results for a particular subclass of problems very often considered in the literature. Basically our method reduces the GNEP to a single penalized (and nonsmooth) Nash equilibrium problem. We suggest a suitable method for the solution of the latter penalized problem and present extensive numerical results. © 2010 Society for Industrial and Applied Mathematics.


Tkachov G.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2013

The paper examines weak localization (WL) of surface states with a quadratic band crossing in topological crystalline insulators. It is shown that the topology of the quadratic band crossing point dictates the negative sign of the WL conductivity correction. For the surface states with broken time-reversal symmetry, an explicit dependence of the WL conductivity on the band Berry flux is obtained and analyzed for different carrier-density regimes and types of the band structure (normal or inverted). These results suggest a way to detect the band Berry flux through WL measurements. © 2013 American Physical Society.


Kranke P.,University of Wurzburg
Cochrane database of systematic reviews (Online) | Year: 2012

Chronic wounds are common and present a health problem with significant effect on quality of life. Various pathologies may cause tissue breakdown, including poor blood supply resulting in inadequate oxygenation of the wound bed. Hyperbaric oxygen therapy (HBOT) has been suggested to improve oxygen supply to wounds and therefore improve their healing. To assess the benefits and harms of adjunctive HBOT for treating chronic ulcers of the lower limb. For this first update we searched the Cochrane Wounds Group Specialised Register (searched 12 January 2012); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4); Ovid MEDLINE (1950 to January Week 1 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations, 11 July 2012); Ovid EMBASE (1980 to 2012 Week 01); and EBSCO CINAHL (1982 to 6 January 2012). Randomised controlled trials (RCTs) comparing the effect on chronic wound healing of therapeutic regimens which include HBOT with those that exclude HBOT (with or without sham therapy). Three review authors independently evaluated the risk of bias of the relevant trials using the Cochrane methodology and extracted the data from the included trials. We resolved any disagreement by discussion. We included nine trials (471 participants). Eight trials (455 participants) enrolled people with a diabetic foot ulcer: pooled data of three trials with 140 participants showed an increase in the rate of ulcer healing (risk ratio (RR) 5.20, 95% confidence interval (CI) 1.25 to 21.66; P = 0.02) with HBOT at six weeks but this benefit was not evident at longer-term follow-up at one year. There was no statistically significant difference in major amputation rate (pooled data of five trials with 312 participants, RR 0.36, 95% CI 0.11 to 1.18). One trial (16 participants) considered venous ulcers and reported data at six weeks (wound size reduction) and 18 weeks (wound size reduction and number of ulcers healed) and suggested a significant benefit of HBOT in terms of reduction in ulcer area only at six weeks (mean difference (MD) 33.00%, 95% CI 18.97 to 47.03, P < 0.00001). We did not identify any trials that considered arterial and pressure ulcers. In people with foot ulcers due to diabetes, HBOT significantly improved the ulcers healed in the short term but not the long term and the trials had various flaws in design and/or reporting that means we are not confident in the results. More trials are needed to properly evaluate HBOT in people with chronic wounds; these trials must be adequately powered and designed to minimise all kinds of bias.


Tkachov G.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2013

The paper proposes a self-consistent Green function description of the induced surface superconductivity in a disordered three-dimensional topological insulator (TI) coupled to an s-wave superconductor. We recover earlier results regarding the induced spin-triplet p-wave pairing, showing that a mixture of p- and s-wave pair correlations appears as a result of broken spin-rotation symmetry on the helical surface of the TI. Unlike the s-wave pairing, the p-wave component is found to be suppressed in dirty TIs in which the elastic mean-free path is much smaller than the superconducting coherence length. The suppression is due to the generic nonlocality of the spin-triplet correlations, which makes them strongly dependent on the mean-free path in a disordered system. In dirty TIs the induced superconductivity is predicted to be predominantly s-wave like. In cleaner TIs, however, the p-wave component may reach a magnitude comparable to (but not larger than) the s-wave pairing. © 2013 American Physical Society.


Greiner J.,MPI Fur Extraterrestrische Physik | Mannheim K.,University of Wurzburg
Experimental Astronomy | Year: 2012

We propose to perform a continuously scanning all-sky survey from 200 keV to 80 MeV achieving a sensitivity which is better by a factor of 40 or more compared to the previous missions in this energy range (COMPTEL, INTEGRAL; see Fig. 1). These gamma-ray observations will be complemented by observations in the soft X-ray and (near-)infrared region with the corresponding telescopes placed on a separate satellite. The Gamma-Ray Imaging, Polarimetry and Spectroscopy ("GRIPS") mission with its three instruments Gamma-Ray Monitor (GRM), X-Ray Monitor (XRM) and InfraRed Telescope (IRT) addresses fundamental questions in ESA's Cosmic Vision plan. Among the major themes of the strategic plan, GRIPS has its focus on the evolving, violent Universe, exploring a unique energy window. We propose to investigate γ-ray bursts and blazars, the mechanisms behind supernova explosions, nucleosynthesis and spallation, the enigmatic origin of positrons in our Galaxy, and the nature of radiation processes and particle acceleration in extreme cosmic sources including pulsars and magnetars. The natural energy scale for these non-thermal processes is of the order of MeV. Although they can be partially and indirectly studied using other methods, only the proposed GRIPS measurements will provide direct access to their primary photons. GRIPS will be a driver for the study of transient sources in the era of neutrino and gravitational wave observatories such as IceCUBE and LISA, establishing a new type of diagnostics in relativistic and nuclear astrophysics. This will support extrapolations to investigate star formation, galaxy evolution, and black hole formation at high redshifts. © 2011 Springer Science+Business Media B.V.


Adamek J.,University of Wurzburg | de Rham C.,University of Geneva | Durrer R.,University of Geneva
Monthly Notices of the Royal Astronomical Society | Year: 2012

We examine the mode functions of the electromagnetic field on spherically symmetric backgrounds with special attention to the subclass which allows for a foliation as open Friedmann-Lemaître (FL) space-time. It is well known that in certain scalar field theories on open FL background there can exist so-called supercurvature modes, their existence depending on parameters of the theory. Looking at specific open universe models, such as open inflation and the Milne universe, we find that no supercurvature modes are present in the spectrum of the electromagnetic field. This excludes the possibility for superadiabatic evolution of cosmological magnetic fields within these models without relying on new physics or breaking the conformal invariance of electromagnetism. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Zernecke A.,University of Wurzburg
Thrombosis and Haemostasis | Year: 2012

Regarded as a chronic inflammatory disease of the vessel wall, the development of atherosclerotic lesions is shaped by immune responses and their regulation. Macrophages and dendritic cells are positioned at the crossroad of innate and adaptive immune responses by sensing atherogenic danger signals and by taking up and presenting antigens. T helper cells and auto-antibodies produced by B cells, together with their cytokine responses in turn modulate atheroprogression. In addition, platelets contribute to atherosclerosis by multiple pathways. microRNAs (miRNAs) that post-transcriptionally regulate gene expression may thus critically control immune cell differentiation and functions during plaque evolution. This review summarises the role of miRNAs in regulating lipid uptake and expression of inflammatory mediators in monocytes/macrophages and dendritic cells, in lymphocyte functions with a focus on T helper cell responses, as well as in platelet biology, and the implications of altering these functions in vascular pathology and atherosclerosis. T systematically survey miRNA functions in controlling molecular mechanisms and immune responses in atherosclerosis holds potential for the development of novel miRNAbased strategies for therapies targeting inflammation and immunity in atherosclerosis. © Schattauer 2012.


A list of the Tettigoniidae (Orthoptera) of the East Usambara Mountains is presented and 16 new species are described from East Africa. A total number of 29 Tettigoniidae species is recorded for the East Usambara Mountains. New species are described from the Shimba Hills in Kenya, coastal Tanzania from the Kazimzumbwi forest reserve, Mt Kilimanjaro, the East and West Usambara and Uluguru Mountains in Tanzania, namely in Conocephalinae Afroagraecia pwania n. sp., Afroagraecia shimbaensis n. sp., Afroanthracites discolor n. sp., Afroanthracites jagoi n. sp. and Afroanthracites viridis n. sp., in Meconematinae Afrophisis flagellata n. sp., Afrophisis kisarawe n. sp., Afrophisis mazumbaiensis n. sp. and Af-rophisis pseudoflagellata n. sp., in Hexacentrinae Aerotegmina megaloptera n. sp., in Mecopodinae Apteroscirtus crista-tus n. sp., and A. planidorsatus n. sp., in Phaneropterinae Gelotopoia amabilis n. sp., and in Pseudophyllinae Cymatomerella pardopunctata n. sp. and Cymatomera viridimaculata n. sp. Seven species are endemic to the East Usam-bara Mountains which are 25% of the recorded forest-bound bush crickets. The Tettigoniidae fauna is compared between the East Usambara Mountains and Mt Kilimanjaro and mechanisms of speciation discussed in Orthoptera for the area. New Tettigoniidae records are given for Mt Kilimanjaro (Oxyecous apertus Ragge, Tropidonotacris grandis Ragge and Eurycorypha conclusa Hemp). Copyright © 2013 Magnolia Press.


Dietl J.,University of Wurzburg
Archives of Gynecology and Obstetrics | Year: 2014

Background Among all gynecological malignancies, ovarian cancer is associated with the highest rate of mortality. Recent findings now propose a pivotal role for the fallopian tube during ovarian cancer pathogenesis. New insights Until recently, ovarian cancer was thought to derive from the ovarian surface epithelium. Nevertheless, attempts to define a precursor lesion from this tissue failed. Instead, prophylactic surgery performed on BRCA mutation carriers and subsequent histological analyses revealed a characteristic pre-neoplastic alteration at the fimbriated end of the fallopian tubes, the so-called serous tubal intraepithelial carcinoma (STIC). By morphology and molecular genetics, STIC was found to resemble serous ovarian cancer. As STIC can also be detected in>60 % of BRCA-unrelated serous ovarian carcinomas, it is now considered to be the precursor of the most common ovarian cancer subtype. Consequences Based on this hypothesis, a salpingectomy, i.e., the removal of the post-reproductive fallopian tubes may remove the actual site of tumorigenesis and thereby prevent spreading over the ovarian surface and throughout the peritoneum. Consequently, prophylactic salpingectomy might protect against serous ovarian cancer. Moreover, the procedure interrupts the connection between the uterine cavity and the lesser pelvis. Hence, it prevents the ascension of exfoliated endometrial cells which will likely reduce the incidence of endometrioid and clear cell ovarian cancers. Increasing evidence suggests that serous ovarian cancer originates from the fimbriated distal end of the fallopian tube, whereas the ovary gets only involved at a later stage. Conclusion Given the lack of suitable screening or early detection strategies for ovarian cancer, post-reproductive salpingectomy deserves serious consideration as a prophylactic intervention that will likely confer significant protection against an often deadly disease. © Springer-Verlag Berlin Heidelberg 2013.


Koepsell H.,University of Wurzburg
Expert Opinion on Drug Metabolism and Toxicology | Year: 2015

Introduction: Organic cation transporters OCT1, OCT2 and OCT3 expressed in the small intestine, liver, brain and other organs play important roles in absorption, excretion and distribution of cationic drugs. Drug-drug interactions at OCTs may change pharmacokinetics, pharmacodynamics and drug toxicity. Knowledge about physiological and biomedical functions of OCTs and the molecular mechanisms of transport and inhibition is required to anticipate drug-drug interactions and their potential biomedical impact.Areas covered: Current knowledge about structure, polyspecific cation binding and transport of OCTs is summarized. Tissue distributions of OCT1-3 and their presumed physiological roles in the small intestine, liver, kidney and brain are reported, and drugs that are transported by human OCT1-3 are listed. The impact of human OCTs for pharmacokinetics and pharmacodynamics of the antidiabetic metformin and antineoplastic platinum derivatives are discussed. In addition, interactions of drugs that are transported by OCTs observed in the kidney and liver are reported. Procedures to test novel drugs for drug-drug interactions at OCTs in vitro and in clinical studies are recommended.Expert opinion: When performing in vitro testing for drug-drug interactions, it must be considered that one inhibitory drug may inhibit different transported drugs with different affinities. After positive in vitro testing for drug-drug interaction, clinical tests are obligatory. © 2015 Informa UK, Ltd.


In patients with isolated peritoneal carcinomatosis (PC) of gastrointestinal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) seem to play a major role in cellular stress during HIPEC therapy. We analyzed differentially hyperthermic conditions and HSPs responsible for cell stress-mediated repair mechanisms in tumor tissues from patients who underwent HIPEC therapy and in an in vitro hyperthermic model. Tumor tissues from our patient cohort with isolated PC were selected for further analysis when representative material was available before and after HIPEC therapy. To further dissect the role of HSPs under conditions of hyperthermia, gene and protein expression was additionally determined, together with cellular apoptosis and proliferation in human HT-29 colon cancer cells. Differently up-regulated HSP70/72 and HSP90 gene and protein expression was found in all investigated patient tumors. In vitro studies confirmed observations from clinical tumor analysis as underlying HSP-mediated cell stress mechanisms. Moreover, results from proliferation and apoptosis assays combined with differentiated HSP expression analysis demonstrated the relevance of preselecting specific target temperatures to achieve optimal toxic effects on remaining tumor cells in vivo. Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis-inducing cellular effects in patients with PC are negatively influenced by highly conserved HSP mechanisms in tumor cells. This study shows for the first time that specific hyperthermic conditions are necessary to be established to achieve optimal toxic effects on tumor cells during HIPEC therapy, a finding that opens potentially new therapeutic strategies.


Zernecke A.,University of Wurzburg | Preissner K.T.,Justus Liebig University
Circulation Research | Year: 2016

Inflammatory and ischemic cardiovascular diseases, especially atherosclerosis and myocardial infarction, remain the number one cause of death in the Western world, whereas the therapeutic options currently available are still limited. Several recent findings have indicated that nucleic acids, particularly extracellular ribosomal RNA and micro-RNAs, significantly contribute to the adverse outcome of atherosclerosis, myocardial infarction, and other cardiovascular diseases. Extracellular RNAs act as novel danger-associated molecular pattern signals and potent cofactors in cardiovascular inflammation and thrombosis, particularly when accumulating in the extracellular space under tissue-damaging or pathological conditions. In this concise review article, the different entities of extracellular RNAs, their cellular sources, and their putative functional contribution to the pathogenesis of cardiovascular diseases will be discussed. In fact, it remains a tightrope walk for these polyanionic molecules outside cells to promote defense reactions on the one side but to provoke cardiovascular disease development on the other side, dependent on their concentration, the environmental conditions, and the cellular stimuli engaged. Thus, we will discuss the mechanisms and cellular responses by which extracellular RNAs operate between defense and disease. Finally, natural counteracting molecules, such as RNase1, will be focused on to elaborate their protective functions in the context of inflammatory and ischemic cardiovascular diseases with the possibility to apply them as novel interventional strategies. ©2016 American Heart Association, Inc.


Lang T.C.,Boston University | Meng Z.Y.,Louisiana State University | Muramatsu A.,University of Stuttgart | Wessel S.,RWTH Aachen | Assaad F.F.,University of Wurzburg
Physical Review Letters | Year: 2013

We study the quantum phases of fermions with an explicit SU(N)-symmetric, Heisenberg-like nearest-neighbor flavor exchange interaction on the honeycomb lattice at half filling. Employing projective (zero temperature) quantum Monte Carlo simulations for even values of N, we explore the evolution from a weak-coupling semimetal into the strong-coupling, insulating regime. Furthermore, we compare our numerical results to a saddle-point approximation in the large-N limit. From the large-N regime down to the SU(6) case, the insulating state is found to be a columnar valence bond crystal, with a direct transition to the semimetal at weak, finite coupling, in agreement with the mean-field result in the large-N limit. At SU(4) however, the insulator exhibits a subtly different valence bond crystal structure, stabilized by resonating valence bond plaquettes. In the SU(2) limit, our results support a direct transition between the semimetal and an antiferromagnetic insulator. © 2013 American Physical Society.


Sauer M.,University of Wurzburg
Chemistry and Biology | Year: 2014

Integration of two fluorescence imaging methods enables tracking of the formation of fibrillar Aβ peptide amyloid aggregates in neurons, as discussed by Esbjörner and colleagues in this issue of Chemistry & Biology. This approach has the potential to fundamentally improve our understanding of the onset and therapeutic intervention of neurodegenerative diseases. © 2014 Elsevier Ltd.


Uceyler N.,University of Wurzburg
BMC musculoskeletal disorders | Year: 2011

To perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, and PsycINFO and screened the reference lists of 22 review articles for suitable original articles. Original articles investigating cytokines in patients with FMS were included. Data were extracted by two independent authors. Differences of the cytokine levels of FMS patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed applying methodological scores: modified Center of Evidence Based Medicine, Newcastle-Ottawa-Scale, and Würzburg Methodological Quality Score. Twenty-five articles were included investigating 1255 FMS patients and 800 healthy controls. Data of 13/25 studies entered meta-analysis. The overall methodological quality of studies was low. The results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed. Systematic review of the selected 25 articles revealed that FMS patients had higher serum levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8, and higher plasma levels of IL-8. Meta-analysis of eligible studies showed that FMS patients had higher plasma IL-6 levels compared to controls (SMD = -0.34 [-0.64, -0.03] 95% CI; p = 0.03). The majority of investigated cytokines were not different between patients and controls. The pathophysiological role of cytokines in FMS is still unclear. Studies of higher quality and with higher numbers of subjects are needed.


Lum J.K.,Medical Research Council Laboratory of Molecular Biology | Neuweiler H.,Medical Research Council Laboratory of Molecular Biology | Neuweiler H.,University of Wurzburg | Fersht A.R.,Medical Research Council Laboratory of Molecular Biology
Journal of the American Chemical Society | Year: 2012

The tumor suppressor p53 is a hub protein with a multitude of binding partners, many of which target its intrinsically disordered N-terminal domain, p53-TAD. Partners, such as the N-terminal domain of MDM2, induce formation of local structure and leave the remainder of the domain apparently disordered. We investigated segmental chain motions in p53-TAD using fluorescence quenching of an extrinsic label by tryptophan in combination with fluorescence correlation spectroscopy (PET-FCS). We studied the loop closure kinetics of four consecutive segments within p53-TAD and their response to protein binding and phosphorylation. The kinetics was multiexponential, showing that the conformational ensemble of the domain deviates from random coil, in agreement with previous findings from NMR spectroscopy. Phosphorylations or binding of MDM2 changed the pattern of intrachain kinetics. Unexpectedly, we found that upon binding and phosphorylation chain motions were altered not only within the targeted segments but also in remote regions. Long-range interactions can be induced in an intrinsically disordered domain by partner proteins that induce apparently only local structure or by post-translational modification. © 2011 American Chemical Society.


Gallant P.,University of Wurzburg
Cold Spring Harbor Perspectives in Medicine | Year: 2013

Drosophila contains a single MYC gene. Like its vertebrate homologs, it encodes a transcription factor that activates many targets, including prominently genes involved in ribosome biogenesis and translation. This activity makes Myc a central regulator of growth and/or proliferation of many cell types, such as imaginal disc cells, polyploid cells, stem cells, and blood cells. Importantly, not only does Myc act cell autonomously but it also affects the fate of adjacent cells and tissues. This potential of Myc is harnessed by many different signaling pathways, involving, among others, Wg, Dpp, Hpo, ecdysone, insulin, and mTOR. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Grundgeiger T.,University of Wurzburg
Memory and Cognition | Year: 2014

Retrieving a subset of learned items can lead to the forgetting of related items. Such retrieval-induced forgetting (RIF) can be explained by the inhibition of irrelevant items in order to overcome retrieval competition when the target item is retrieved. According to the retrieval inhibition account, such retrieval competition is a necessary condition for RIF. However, research has indicated that noncompetitive retrieval practice can also cause RIF by strengthening cue-item associations. According to the strength-dependent competition account, the strengthened items interfere with the retrieval of weaker items, resulting in impaired recall of weaker items in the final memory test. The aim of this study was to replicate RIF caused by noncompetitive retrieval practice and to determine whether this forgetting is also observed in recognition tests. In the context of RIF, it has been assumed that recognition tests circumvent interference and, therefore, should not be sensitive to forgetting due to strength-dependent competition. However, this has not been empirically tested, and it has been suggested that participants may reinstate learned cues as retrieval aids during the final test. In the present experiments, competitive practice or noncompetitive practice was followed by either final cued-recall tests or recognition tests. In cued-recall tests, RIF was observed in both competitive and noncompetitive conditions. However, in recognition tests, RIF was observed only in the competitive condition and was absent in the noncompetitive condition. The result underscores the contribution of strength-dependent competition to RIF. However, recognition tests seem to be a reliable way of distinguishing between RIF due to retrieval inhibition or strength-dependent competition. © 2013 Psychonomic Society, Inc.


Totipotent somatic stem cells (neoblasts) are key players in the biology of flatworms and account for their amazing regenerative capability and developmental plasticity. During recent years, considerable progress has been made in elucidating molecular features of neoblasts from free-living flatworms, whereas their role in parasitic species has so far merely been addressed by descriptive studies. Very recently, however, significant advances have been made in the in vitro culture of neoblasts from the cestode Echinococcus multilocularis. The isolated cells proved capable of generating mature metacestode vesicles under laboratory conditions in a manner that closely resembles the oncosphere-metacestode transition during natural infections. Using the established neoblast cultivation protocols, combined with targeted manipulation of Echinococcus genes by RNA-interference, several fundamental questions of host-dependent parasite development can now be addressed. Here, I give an overview of current cultivation techniques for E. multilocularis neoblasts and present experimental approaches to study their function. Furthermore, I introduce the E. multilocularis genome sequencing project that is presently in an advanced stage. The combined input of data from the E. multilocularis sequencing project, stem cell cultivation, and recently initiated attempts to genetically manipulate Echinococcus will provide an ideal platform for hypothesis-driven research into cestode development in the next years. © 2009 Cambridge University Press.


Kramer S.,University of Wurzburg
Wiley Interdisciplinary Reviews: RNA | Year: 2014

Ribonucleoprotein (RNP) granules are important posttranscriptional regulators of messenger RNA (mRNA) fate. Several types of RNP granules specifically regulate gene expression during development of multicellular organisms and are commonly referred to as germ granules. The function of germ granules is not entirely understood and probably diverse, but it is generally agreed that one main function is posttranscriptional regulation of gene expression during early development, when transcription is silent. One example is the translational repression of maternally derived mRNAs in oocytes. Here, I hope to show that the need for regulation of gene expression by RNP granules is not restricted to animal development, but plays an equally important role during the development of pathogenic protozoa. Apicomplexa and Trypanosomatidae have complex life cycles with frequent host changes. The need to quickly adapt gene expression to a new environment as well as the ability to suppress translation to survive latencies is critical for successful completion of life cycles. Posttranscriptional gene regulation is not necessarily simpler in protozoa. Apicomplexa surprise with the presence of micro RNA (miRNAs) and upstream open reading frames (μORFs). Trypanosomes have an unusually large repertoire of different RNP granule types. A better understanding of RNP granules in protozoa may help to gain insight into the evolutionary origin of RNP granules: Trypanosomes for example have two types of granules with interesting similarities to animal germ granules. © 2013 John Wiley & Sons, Ltd.


Trujillo M.,University of Wurzburg | Shirasu K.,RIKEN
Current Opinion in Plant Biology | Year: 2010

Plant immune responses require the coordination of a myriad of processes that are triggered upon perception of invading pathogens. Ubiquitin, the ubiquitination system (UBS) and the 26S proteasome are key for the regulation of processes such as the oxidative burst, hormone signaling, gene induction, and programmed cell death. E3 ligases, the specificity determinants of ubiquitination, have received by far the most attention. Several single-unit ligases, which are rapidly induced by biotic cues, function as both positive and negative regulators of immune responses, whereas multisubunit ligases are mainly involved in hormone signaling. An increasing body of evidence emphasizes the heavy targeting of the UBS by pathogen virulence effectors, underlining its importance in immunity. © 2010 Elsevier Ltd.


Wetzel A.,University of Wurzburg
Channels (Austin, Tex.) | Year: 2013

Spontaneous electrical activity preceding synapse formation contributes to the precise regulation of neuronal development. Examining the origins of spontaneous activity revealed roles for neurotransmitters that depolarize neurons and activate ion channels. Recently, we identified a new molecular mechanism underlying fluctuations in spontaneous neuronal excitability. We found that embryonic motoneurons with a genetic loss of the low-threshold sodium channel NaV1.9 show fewer fluctuations in intracellular calcium in axonal compartments and growth cones than wild-type littermates. As a consequence, axon growth of NaV1.9-deficient motoneurons in cell culture is drastically reduced while dendritic growth and cell survival are not affected. Interestingly, NaV1.9 function is observed under conditions that would hardly allow a ligand- or neurotransmitter-dependent depolarization. Thus, NaV1.9 may serve as a cell-autonomous trigger for neuronal excitation. In this addendum, we discuss a model for the interplay between cell-autonomous local neuronal activity and local cytoskeleton dynamics in growth cone function.


Haigis W.,University of Wurzburg
Saudi Journal of Ophthalmology | Year: 2012

The introduction of new intraocular lenses (IOLs), industry marketing to the public and patient expectations has warranted increased accuracy of IOL power calculations. Toric IOLs, multifocal IOLs, aspheric IOLs, phakic lenses, accommodative lenses, cases of refractive lens exchange and eyes that have undergone previous refractive surgery all require improved clinical measurements and IOL prediction formulas. Hence, measurement techniques and IOL calculation formulas are essential factors that affect the refractive outcome. Measurement with ultrasound has been the historic standard for measurement of ocular parameters for IOL calculation. However the introduction of optical biometry using partial coherence interferometry (PCI) has steadily established itself as the new standard. Additionally, modern optical instruments such as Scheimpflug cameras and optical coherence tomographers are being used to determine corneal power that was normally the purview of manual keratometry and topography. A number of methods are available to determine the IOL power including the empirical, analytical, numerical or combined methods. Ray tracing techniques or paraxial approximation by matrix methods or classical analytical 'IOL formulas' are actively used in for the prediction of IOL power. There is no universal formula for all cases - phakic and pseudophakic cases require different approaches, as do short eyes, long eyes, astigmatic eyes or post-refractive surgery eyes. Invariably, IOLs are characterized by different methods and lens constants, which require individual optimization. This review describes the current methods for biometry and IOL calculation. © 2012 Saudi Ophthalmological Society, King Saud University.


Breuning M.,University of Bayreuth | Hein D.,University of Wurzburg
European Journal of Organic Chemistry | Year: 2013

5-Mono- and 5,5-disubstituted tricyclic bispidines, derivatives of the known (+)-sparteine surrogate, have been synthesized in four-to-six steps from the natural alkaloid (-)-cytisine and evaluated as chiral ligands in the enantioselective lithiation/stannylation of an O-alkyl carbamate. Structure-selectivity studies revealed that a small 5-endo substituent is tolerated, whereas larger 5-endo substituents and even small 5-exo substituents lead to significantly reduced levels of chirality transfer. Novel tricyclic bispidines have been synthesized from the readily available alkaloid (-)-cytisine and evaluated in the enantioselective lithiation/stannylation of an O-alkyl carbamate. Structure-selectivity studies revealed that an increased steric demand at the 5-endo position is not favorable. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Ruczynski I.,Polish Academy of Sciences | Barton K.A.,University of Wurzburg
PLoS ONE | Year: 2012

Sensory limitation plays an important role in the evolution of animal behaviour. Animals have to find objects of interest (e.g. food, shelters, predators). When sensory abilities are strongly limited, animals adjust their behaviour to maximize chances for success. Bats are nocturnal, live in complex environments, are capable of flight and must confront numerous perceptual challenges (e.g. limited sensory range, interfering clutter echoes). This makes them an excellent model for studying the role of compensating behaviours to decrease costs of finding resources. Cavity roosting bats are especially interesting because the availability of tree cavities is often limited, and their quality is vital for bats during the breeding season. From a bat's sensory point of view, cavities are difficult to detect and finding them requires time and energy. However, tree cavities are also long lasting, allowing information transfer among conspecifics. Here, we use a simple simulation model to explore the benefits of tree selection, memory and eavesdropping (compensation behaviours) to searches for tree cavities by bats with short and long perception range. Our model suggests that memory and correct discrimination of tree suitability are the basic strategies decreasing the cost of roost finding, whereas perceptual range plays a minor role in this process. Additionally, eavesdropping constitutes a buffer that reduces the costs of finding new resources (such as roosts), especially when they occur in low density. We conclude that natural selection may promote different strategies of roost finding in relation to habitat conditions and cognitive skills of animals. © 2012 Ruczynski, Bartoń.


Wanner C.,University of Wurzburg | Tonelli M.,University of Alberta
Kidney International | Year: 2014

The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed clinical practice guidelines on lipid management for all adults and children with chronic kidney disease (CKD). Thirteen recommendations were obtained from the available evidence outlining a three-step management including assessment in all, treatment in many, and follow-up measurements in few. A key element is the recommendation of statin or statin/ezetimibe treatment in adults aged ≥50 years with estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 but not treated with chronic dialysis or kidney transplantation. In dialysis patients, the magnitude of any relative reduction in risk appears to be substantially smaller than in earlier stages of CKD and initiation of statin treatment is not recommended for most prevalent hemodialysis patients. In the past, clinical practice guidelines suggested the use of targets for LDL cholesterol, which require repeated measurements. Treatment escalation with higher doses of statin would be a consequence when LDL cholesterol targets are not met. The KDIGO Work Group did not recommend this strategy because higher doses of statins have not been proven to be safe in the setting of CKD. Since LDL cholesterol levels do not necessarily suggest the need to increase statin doses, follow-up measurement of lipid levels is not recommended. © 2014 International Society of Nephrology.


Sturm C.,University of Wurzburg
Nuclear and Particle Physics Proceedings | Year: 2015

We discuss the determination of the heavy charm- and bottom-quark masses from the sum rule approach as well as the determination of the strong coupling constant from the measurable R-ratio, hadronic τ-lepton decays and Z-boson decays. From theory side these determinations require the calculation of the vacuum polarization function in the low- and high-energy limit, respectively. © 2015 Elsevier B.V.


To evaluate oncological and clinical outcome in patients with renal cell carcinoma (RCC) and tumor thrombus involving inferior vena cava (IVC) treated with nephrectomy and thrombectomy. We identified 50 patients with a median age of 65 years, who underwent radical surgical treatment for RCC and tumor thrombus of the IVC between 1997 and 2010. The charts were reviewed for pathological and surgical parameters, as well as complications and oncological outcome. The median follow-up was 26 months. In 21 patients (42%) distant metastases were already present at the time of surgery. All patients underwent radical nephrectomy, thrombectomy and lymph node dissection through a flank (15 patients/30%), thoracoabdominal (14 patients/28%) or midline abdominal approach (21 patients/42%), depending upon surgeon preference and upon the characteristics of tumor and associated thrombus. Extracorporal circulation with cardiopulmonary bypass (CPB) was performed in 10 patients (20%) with supradiaphragmal thrombus of IVC. Cancer-specific survival for the whole cohort at 5 years was 33.1%. Survival for the patients without distant metastasis at 5 years was 50.7%, whereas survival rate in the metastatic group at 5 years was 7.4%. Median survival of patients with metastatic disease was 16.4 months.On multivariate analysis lymph node invasion, distant metastasis and grading were independent prognostic factors. There was no statistically significant influence of level of the tumor thrombus on survival rate. Indeed, patients with supradiaphragmal tumor thrombus (n = 10) even had a better outcome (overall survival at 5 years of 58.33%) than the entire cohort. An aggressive surgical approach is the most effective therapeutic option in patients with RCC and any level of tumor thrombus and offers a reasonable longterm survival. Due to good clinical and oncological outcome we prefer the use of CPB with extracorporal circulation in patients with supradiaphragmal tumor thrombus. Cytoreductive surgery appears to be beneficial for patients with metastatic disease, especially when consecutive therapy is performed. Although sample size of our study cohort is limited consistent with some other studies lymph node invasion, distant metastasis and grading seem to have prognostic value.


Herbort O.,University of Wurzburg
Human Movement Science | Year: 2015

When humans grasp objects, the grasps foreshadow the intended object manipulation. It has been suggested that grasps are selected that lead to medial arm postures, which facilitate movement speed and precision, during critical phases of the object manipulation. In Experiment 1, it has been tested whether grasp selections lead to medial postures during rotations of a dial. Participants twisted their arms considerably before grasping the dial, even when the upcoming dial rotation was minimal (5°). Participants neither assumed a medial posture at any point during a short rotation, nor did they assume any of the postures involved in short rotations in the opposite direction. Thus, grasp selections did not necessarily lead to specific postures at any point of the object manipulation. Experiment 2 examined the effect of various grasps on the speed of dial rotations. A medial initial grasp resulted in the fastest dial rotations for most rotation angles. Spontaneously selected grasps were more excursed than necessary to maximize dial rotation speed. This apparent overshot might be explained by participants' sensitive to the variability of their grasps and is in line with the assumption that grasps facilitate control over the grasped object. © 2015 Elsevier B.V.


Michels B.,University of Wurzburg
Learning & memory (Cold Spring Harbor, N.Y.) | Year: 2011

Synapsin is an evolutionarily conserved, presynaptic vesicular phosphoprotein. Here, we ask where and how synapsin functions in associative behavioral plasticity. Upon loss or reduction of synapsin in a deletion mutant or via RNAi, respectively, Drosophila larvae are impaired in odor-sugar associative learning. Acute global expression of synapsin and local expression in only the mushroom body, a third-order "cortical" brain region, fully restores associative ability in the mutant. No rescue is found by synapsin expression in mushroom body input neurons or by expression excluding the mushroom bodies. On the molecular level, we find that a transgenically expressed synapsin with dysfunctional PKA-consensus sites cannot rescue the defect of the mutant in associative function, thus assigning synapsin as a behaviorally relevant effector of the AC-cAMP-PKA cascade. We therefore suggest that synapsin acts in associative memory trace formation in the mushroom bodies, as a downstream element of AC-cAMP-PKA signaling. These analyses provide a comprehensive chain of explanation from the molecular level to an associative behavioral change.


Contrast-enhanced ultrasound (CEUS) is a well established diagnostic imaging technique for a variety of indications and applications. One of the most important applications is in the liver where it is frequently a first-line technique for the detection and diagnosis (characterization) of focal liver lesions (FLLs). In this setting the accurate differentiation of benign lesions from malignant lesions is critical to ensure that the patient undergoes the appropriate therapeutic option. In this article the role of CEUS in the characterization of FLLs is described on the basis of recently published guidelines, in particular in terms of the enhancement patterns of the most common FLLs, e. g. hemangioma, focal nodular hyperplasia, hepatocellular adenoma and their differentiation from malignant lesions. © Georg Thieme Verlag KG.


Seibel J.,University of Wurzburg
Advances in carbohydrate chemistry and biochemistry | Year: 2010

Oligosaccharides and polysaccharides have found manifold interests in the fields of food, pharmaceuticals, and cosmetics as a result of their various specific properties. Food, sweeteners, and food ingredients constitute important sectors where oligosaccharides are used in substantial amounts. Large amounts of sucrose isomers and derivatives, as well as major amounts of fructo-oligosaccharides are commercialized in Europe and worldwide as sweeteners, prebiotics, and other uses. Increasing attention has been devoted to the sophisticated roles of oligosaccharides and glycosylated compounds at cell or membrane surfaces, and their function, as in infection and cancer proliferation. The challenge for synthetic access is obvious, and convenient approaches using cheap and readily available substrates and enzymes are discussed here. Important examples of commercialized products and recent promising developments are presented in this chapter.


Liu X.,University of Wurzburg
International Journal of Industrial Organization | Year: 2016

Innovation is a driving force for most industries, where it moreover affects many stages of the vertical chain. We study the impact of vertical integration on innovation in an industry where firms need to undertake risky R&D investments at both production and distribution stages. Vertical integration brings better coordination within the integrated firm, which boosts its investment incentive at both upstream and downstream levels. However, it is only mutually beneficial for firms to integrate when both upstream and downstream innovations are important. When innovation is irrelevant at one level, firms favor instead vertical separation. The analysis provides insights for the wave of mergers and R&D outsourcing observed in the pharmaceutical industry and other vertically related industries. © 2016 Elsevier B.V. All rights reserved.


Zwanzger P.,University of Munster | Domschke K.,University of Munster | Domschke K.,University of Wurzburg | Bradwejn J.,University of Ottawa
Depression and Anxiety | Year: 2012

Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD. © 2012 Wiley Periodicals, Inc.


Maiden M.C.J.,University of Oxford | Frosch M.,University of Wurzburg
Vaccine | Year: 2012

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. © 2011 Elsevier Ltd.


Almeling S.,European Directorate for the Quality of Medicines and Health Care | Holzgrabe U.,University of Wurzburg
Journal of Chromatography A | Year: 2010

High performance liquid chromatography (HPLC) with evaporative light scattering detection (ELSD) is a versatile, easy to use and inexpensive alternative when it comes to the analysis of substances lacking a chromophor for UV detection. However, in pharmaceutical analysis injection of highly concentrated test solutions are normally required to control impurities at low levels. Under these conditions spike peaks were observed in the chromatograms of the test solutions making a proper evaluation of the impurity profile impossible. The influence of different eluent and ELSD parameters such as eluent composition, eluent flow-rate, ELSD scavenger gas flow-rate and evaporation temperature on the appearance of spike peaks was investigated. It could be shown that spike peaks can be avoided when selecting elevated eluent flow-rates and ESLD scavenger gas flow-rates. Moreover, eluents containing high amounts of organic modifier seem to foster the appearance of spike peaks. © 2010 Elsevier B.V. All rights reserved.


Boons F.,Erasmus University Rotterdam | Montalvo C.,TNO | Quist J.,Technical University of Delft | Wagner M.,University of Wurzburg
Journal of Cleaner Production | Year: 2013

Sustainable development requires radical and systemic innovations. Such innovations can be more effectively created and studied when building on the concept of business models. This concept provides firms with a holistic framework to envision and implement sustainable innovations. For researchers, the concept provides an analytical tool that allows them to assess the interplay between the different aspects that firms combine to create ecological, economic, and social value. In addition, the business model concept provides a link between the individual firm and the larger production and consumption system in which it operates. This paper provides an introduction to the special issue, which emerged from selected papers presented at the ERSCP-EMSU 2010 Conference held in Delft, The Netherlands. Papers in the special issue cover a broad range, from a conceptual discussion resulting in a research agenda, the assessment of diffusion of specific business models such as Product-Service Systems, the introduction of new management tools for business transition management, to case studies on how specific business models evolved in specific communities. Together, these papers provide insight into the promise of the business model concept for understanding and advancing sustainable innovation. © 2013 Published by Elsevier Ltd.


Werner H.,University of Wurzburg
Angewandte Chemie - International Edition | Year: 2013

Numerous honors were bestowed on Alfred Werner, who in 1913 was the first Swiss scientist to be awarded the Nobel Prize in Chemistry. This Essay gives an overview of Werner's scientific work and its significance beyond coordination chemistry. Picture: gray Co, red O, blue N, yellow H. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Wagner M.,University of Wurzburg | Wagner M.,University of Strasbourg
Ecological Economics | Year: 2010

This paper analyses the link between sustainability management and economic performance. Its main research question concerns the association of social responsibility and environmental management with economic performance, determinants of the latter and possible moderation effects. Based on data collected from financial databases and Kinder Lydenberg Domini for the period 1992 to 2003, the paper analyses the link of corporate sustainability performance with economic performance using panel estimation techniques. The analysis shows that advertising intensity moderates the association of corporate sustainability performance and economic performance as measured by Tobin's q. For research and development efforts relative to firm size, no moderating role on the link between corporate sustainability and economic performance is identified. A sensitivity analysis using separate measures for social and environmental performance reveals that the latter only has a direct effect and the former only a fully moderated effect on economic performance. Policy and management implications of these findings are discussed. © 2010 Elsevier B.V. All rights reserved.


Richter S.,University of Wurzburg | Spanier F.,North West University South Africa
Astroparticle Physics | Year: 2015

Very fast variability on scales of minutes is regularly observed in Blazars. The assumption that these flares are emerging from the dominant emission zone of the very high energy (VHE) radiation within the jet challenges current acceleration and radiation models. In this work we use a spatially resolved and time dependent synchrotron-self-Compton (SSC) model that includes the full time dependence of Fermi-I acceleration. We use the (apparent) orphan γ-ray flare of Mrk501 during MJD 54952 and test various flare scenarios against the observed data. We find that a rapidly variable external radiation field can reproduce the high energy lightcurve best. However, the effect of the strong inverse Compton (IC) cooling on other bands and the X-ray observations are constraining the parameters to rather extreme ranges. Then again other scenarios would require parameters even more extreme or stronger physical constraints on the rise and decay of the source of the variability which might be in contradiction with constraints derived from the size of the black hole's ergosphere.


Lutz M.B.,University of Wurzburg
Frontiers in Immunology | Year: 2012

Dendritic cells (DCs) are major players in the control of adaptive tolerance and immunity. Therefore, their specific generation and adoptive transfer into patients or their in vivo targeting is attractive for clinical applications. While injections of mature immunogenic DCs are tested in clinical trials, tolerogenic DCs still are awaiting this step. Besides the tolerogenic potential of immature DCs, also semi-mature DCs can show tolerogenic activity but both types also bear unfavorable features. Optimal tolerogenic DCs, their molecular tool bar, and their use for specific diseases still have to be defined. Here, the usefulness of in vitro generated and adoptively transferred semi-mature DCs for tolerance induction is outlined. The in vivo targeting of semi-mature DCs as represented by steady state migratory DCs are discussed for treatment of autoimmune diseases and allergies. First clinical trials with transcutaneous allergen application may point to their therapeutic use in the future. © 2012 Lutz.


Tvingstedt K.,University of Wurzburg | Deibel C.,TU Chemnitz
Advanced Energy Materials | Year: 2016

The value and temperature dependence of the ideality factor provides essential information about the dominant recombination route in solar cells. This study presents experimental results of accurate ideality factor determination for representative organic photovoltaic cells (OPV) evaluated at different temperatures over a large current density regime. It is noted that standard dark I-V curves strongly deviate from those obtained by evaluations based on short circuit current density (J SC)-open circuit voltage (V OC) pairs. This is attributed to the applied external voltage in a dark I-V measurement not being representative of internal chemical potential, particularly at lower temperatures. Complementary electroluminescence measurements attest that the current density dependence of the ability of the solar cell to emit light is better correlated to the series resistance free ideality factor. For the studied set of OPV devices it is observed that the ideality factors are quite low, and with very weak temperature dependence. The J SC-V OC method to determine ideality factors further allows good estimates of activation energies as well as recombination current prefactors J 00. The findings imply that the principal OPV non-radiative recombination mechanism is not recombination of free carriers with trapped carriers in an exponential density of tail states as previously reported. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Wolfl M.,University of Wurzburg | Greenberg P.D.,Fred Hutchinson Cancer Research Center | Greenberg P.D.,University of Washington
Nature Protocols | Year: 2014

Antigen-specific priming of human, naive T cells has been difficult to assess. Owing to the low initial frequency in the naive cell pool of specific T cell precursors, such an analysis has been obscured by the requirements for repeated stimulations and prolonged culture time. In this protocol, we describe how to evaluate antigen-specific priming of CD8+ cells 10 d after a single specific stimulation. The assay provides reference conditions, which result in the expansion of a substantial population of antigen-specific T cells from the naive repertoire. Various conditions and modifications during the priming process (e.g., testing new cytokines, co-stimulators and so on) can now be directly compared with the reference conditions. Factors relevant to achieving effective priming include the dendritic cell preparation, the T cell preparation, the cell ratio at the time of priming, the serum source used for the experiment and the timing of addition and concentration of the cytokines used for expansion. This protocol is relevant for human immunology, vaccine biology and drug development. © 2014 Nature America, Inc. All rights reserved.


Laufer S.,University of Tubingen | Holzgrabe U.,University of Wurzburg | Steinhilber D.,Goethe University Frankfurt
Angewandte Chemie - International Edition | Year: 2013

The increasing costs as well as the lack of innovation potency in the development of new drugs have led to a discussion of the possible contribution of the German university landscape, especially pharmaceutical sciences. Successful examples are already apparent in the US. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Grafahrend D.,RWTH Aachen | Heffels K.-H.,RWTH Aachen | Beer M.V.,RWTH Aachen | Gasteier P.,RWTH Aachen | And 6 more authors.
Nature Materials | Year: 2011

Advanced biomaterials and scaffolds for tissue engineering place high demands on materials and exceed the passive biocompatibility requirements previously considered acceptable for biomedical implants. Together with degradability, the activation of specific cell-material interactions and a three-dimensional environment that mimics the extracellular matrix are core challenges and prerequisites for the organization of living cells to functional tissue. Moreover, although bioactive signalling combined with minimization of non-specific protein adsorption is an advanced modification technique for flat surfaces, it is usually not accomplished for three-dimensional fibrous scaffolds used in tissue engineering. Here, we present a one-step preparation of fully synthetic, bioactive and degradable extracellular matrix-mimetic scaffolds by electrospinning, using poly(D,L-lactide-co-glycolide) as the matrix polymer. Addition of a functional, amphiphilic macromolecule based on star-shaped poly(ethylene oxide) transforms current biomedically used degradable polyesters into hydrophilic fibres, which causes the suppression of non-specific protein adsorption on the fibresĝ€™ surface. The subsequent covalent attachment of cell-adhesion-mediating peptides to the hydrophilic fibres promotes specific bioactivation and enables adhesion of cells through exclusive recognition of the immobilized binding motifs. This approach permits synthetic materials to directly control cell behaviour, for example, resembling the binding of cells to fibronectin immobilized on collagen fibres in the extracellular matrix of connective tissue. © 2011 Macmillan Publishers Limited. All rights reserved.


Lassmann M.,University of Wurzburg | Treves S.T.,Brigham and Womens Hospital
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

In 2008 the EANM published their paediatric dosage card. In 2011 the North American consensus guidelines recommended a set of administered activities for paediatric nuclear medicine. During the EANM congress in 2012 a working group of the EANM and the SNMMI met to study the possibility of harmonizing these guidelines. The purpose of this work was to identify differences between these guidelines and suggest changes in both guidelines to achieve a level of harmonization. In addition, the new version of the EANM paediatric dosage card (version 01.02.2014) is provided. © 2014 Springer-Verlag Berlin Heidelberg.


Assaad F.F.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2015

We show that the two recently proposed methods to compute Renyi entanglement entropies in the realm of determinant quantum Monte Carlo methods for fermions are in principle equivalent, but differ in sampling strategies. The analogy allows us to formulate a numerically stable calculation of the entanglement spectrum at strong coupling. We demonstrate the approach by studying static and dynamical properties of the entanglement Hamiltonian across the interaction driven quantum phase transition between a topological insulator and quantum antiferromagnet in the Kane-Mele Hubbard model. The formulation is not limited to fermion systems and can readily be adapted to world-line-based simulations of bosonic systems. © 2015 American Physical Society.


Li G.,University of Wurzburg
Physical Review B - Condensed Matter and Materials Physics | Year: 2015

In this work, we present a nonlocal expansion scheme to study correlated electron systems aiming at a better description of its spatial fluctuations at all length scales. Taking the nonlocal coupling as a perturbation to the local degrees of freedom, we show that the nonlocality in the self-energy function can be efficiently constructed from the coupling between local fluctuations. It can provide one unified framework to incorporate nonlocality to both ordered and disordered correlated many-body fermion systems. In this application, we prove that the dual-fermion approach can be understood as a special case of this nonlocal expansion scheme. The scheme presented in this work is constructed without introducing any dual variable, in which the interacting nature and the correlated behaviors of the lattice fermions have a clear physics correspondence. Thus, in this special case, the equivalence of the dual-fermion approach to the nonlocal expansion scheme beautifully reveals the physics origin of the dual variables. We show that the noninteracting dual-fermion Green's function corresponds exactly to a nonlocal coupling of the lattice fermion renormalized by the local single-particle charge fluctuations, and the dual-fermion self-energy behaves as the one-particle fully irreducible components of the lattice Green's function. Not only limited to this specific example, the nonlocal expansion scheme presented in this work can also be applied to other problems depending on the choice of the local degrees of freedom. © 2015 American Physical Society.


Haaf E.,Center for Biological Systems Analysis | Schlosser A.,Center for Biological Systems Analysis | Schlosser A.,University of Wurzburg
Analytical Chemistry | Year: 2012

We have developed a new method that applies acidic catalysis with hydrochloric acid for 18O-labeling of peptides at their carboxyl groups. With this method, peptides get labeled at their C-terminus, at Asp and Glu residues, and at carboxymethylated cysteine residues. Oxygen atoms at phosphate groups of phosphopeptide are not exchanged. Our elaborated labeling protocol is easy to perform, fast (5 h and 30 min), and results in 95-97 atom % incorporation of 18O at carboxyl groups. Undesired side reactions, such as deamidation or peptide hydrolysis, occur only at a very low level under the conditions applied. In addition, data analysis can be performed automatically using common software tools, such as Mascot Distiller. We have demonstrated the capability of this method for the quantitation of peptides as well as for phosphopeptides. © 2011 American Chemical Society.


Holmoy T.,University of Oslo | Geis C.,University of Wurzburg
Journal of Neuroimmunology | Year: 2011

Antibodies against autoantigens involved in GABAergic neurotransmission are a shared feature of the different subtypes of stiff person syndrome (SPS). The autoantigens can be either presynaptic such as the smaller isoform of glutamic acid decarboxylase (GAD65), postsynaptic such as GABA-A receptor-associated protein and gephyrin, or located at the pre- and postsynaptic side such as amphiphysin. Most of these autoantigens are intracellular, and antibodies against GAD65 also occur in diabetes mellitus type 1 as well as other neurological diseases. Their pathogenic role has therefore been questioned. We here discuss the role of autoantibodies and T cells in SPS. © 2010 Elsevier B.V.


Adamek J.,University of Wurzburg | Campo D.,University of Gottingen | Niemeyer J.C.,University of Gottingen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2010

In a landscape of compactifications with different numbers of macroscopic dimensions, it is possible that our Universe has nucleated from a vacuum where some of our four large dimensions were compact while other, now compact, directions were macroscopic. From our perspective, this shapeshifting can be perceived as an anisotropic background spacetime. As an example, we present a model where our Universe emerged from a tunneling event which involves the decompactification of two dimensions compactified on the two-sphere. In this case, our Universe is of the Kantowski-Sachs type and therefore homogeneous and anisotropic. We study the deviations from statistical isotropy of the cosmic microwave background induced by the anisotropic curvature, with particular attention to the anomalies. The model predicts a quadrupolar power asymmetry with the same sign and acoustic oscillations as found by the Wilkinson Microwave Anisotropy Probe. The amplitude of the effect is however too small given the current estimated bound on anisotropic curvature derived from the quadrupole. © 2010 The American Physical Society.


Djouadi A.,University Paris - Sud | Moreau G.,University Paris - Sud | Richard F.,University Paris - Sud | Singh R.K.,University of Wurzburg
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2010

The CDF and D0 experiments have reported on the measurement of the forward-backward asymmetry of top quark pair production at the Tevatron and the result is that it is more than 2 standard deviations above the predicted value in the standard model. This has to be added to the long-standing anomaly in the forward-backward asymmetry for bottom quark production at LEP which is 3 standard deviations different from the standard model value. The discrepancy in the bottom asymmetry can be accounted for by the contributions of Kaluza-Klein excitations of electroweak gauge bosons at LEP in warped extra-dimensional models in which the fermions are localized differently along the extra dimension so that the gauge interactions of heavy third generation fermions are naturally different from that of light fermions. In this paper, we show that it is more difficult to elaborate a model generating a significant top asymmetry through exchanges of Kaluza-Klein gluons at the Tevatron due to the indirect constraints originating from precision electroweak data. © 2010 The American Physical Society.


Benhar O.,National Institute of Nuclear Physics, Italy | Benhar O.,University of Rome La Sapienza | Coletti P.,University of Rome La Sapienza | Meloni D.,University of Wurzburg
Physical Review Letters | Year: 2010

The availability of the double-differential charged-current neutrino cross section, measured by the MiniBooNE Collaboration by using a carbon target, allows for a systematic comparison of nuclear effects in quasielastic electron and neutrino scattering. The results of our study, based on the impulse approximation scheme and a state-of-the-art model of the nuclear spectral functions, suggest that the electron cross section and the flux averaged neutrino cross sections, corresponding to the same target and comparable kinematical conditions, cannot be described within the same theoretical approach using the value of the nucleon axial mass obtained from deuterium measurements. We analyze the assumptions underlying the treatment of electron-scattering data and argue that the description of neutrino data will require a new paradigm, suitable for application to processes in which the lepton kinematics is not fully determined. © 2010 The American Physical Society.


A list of the Tettigoniidae and Gryllacrididae (Orthoptera: Ensifera) of Mt Kilimanjaro is presented. A total number of 63 Ensifera was recorded for this mountain, of which 25 species belonged to Phaneropterinae, 18 to Conocephalinae, 6 to Hetrodinae and three to Pseudophyllinae. The subfamily Meconematinae contributed two species while only one species of the subfamilies Hexacentrinae, Mecopodinae and Saginae was found. Gryllacrididae contributed six species. Three species recorded in literature were not found again during the research period. 15 species are newly recorded for Mt Kilimanjaro in this study and one species of Agraeciini newly described. Two new genera, Afroanthracites Hemp and Ingrisch n. gen. (type species: Anthracites montium Sjöstedt, 1910) and Afroagraecia Ingrisch and Hemp n. gen. (type species: Agraecia sansibara Redtenbacher, 1891), are erected on African Agraeciini (Conocephalinae). Anthracites kilimandjaricus Sjöstedt, 1910 is snonymized with A. montium Sjöstedt, 1910. Agraecia sansibara (Redtenbacher, 1891), Anthracites bloyeti Brongniart, 1897 and Anelytra panteli Karny are transferred to Afroagraecia. Aethiomerus stenorhinus Saussure, 1899 is synonymised with Afroagraecia sansibara (Redtenbacher, 1891). In Caelifera two Catantopinae (Acrididae) species are newly recorded for Mt Kilimanjaro and one pyrgomorphid species, Maura lurida (Fabricius, 1781), recovered again for the area. © 2013 Magnolia Press.


Schlegel N.,University of Wurzburg | Waschke J.,Ludwig Maximilians University of Munich
Cell and Tissue Research | Year: 2014

cAMP is one of the most potent signaling molecules to stabilize the endothelial barrier, both under resting conditions as well as under challenge of barrier-destabilizing mediators. The two main signaling axes downstre