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Tubingen, Germany

Eberhard Karls University, Tübingen is a public research university located in the city of Tübingen, Baden-Württemberg. It is one of Germany's most famous and oldest universities, internationally noted in medicine, natural science, and the humanities. In the area of German Studies it has been ranked first among all German universities for many years, and is known as a centre for the study of theology and religion. Tübingen is one of five classical "university towns" in Germany; the other four being Marburg, Göttingen, Freiburg and Heidelberg. The university is associated with some Nobel laureates, especially in the fields of medicine and chemistry. Wikipedia.

From the homotopy groups of three distinct octahedral spherical three-manifolds we construct the isomorphic groups H of deck transformations acting on the three-sphere. The H-invariant polynomials on the three-sphere constructed by representation theory span the bases for the harmonic analysis on three spherical manifolds. Analysis of the Cosmic Microwave Background in terms of these new bases can reveal a non-simple topology of the space part of space-time. © 2010 The Royal Swedish Academy of Sciences.

Whelan E.T.,University of Tubingen
Astronomische Nachrichten | Year: 2014

The protostellar outflow mechanism operates for a significant fraction of the pre-main sequence phase of a solar mass star and is thought to have a key role in star and perhaps even planet formation. This energetic mechanism manifests itself in several different forms and on many scales. Thus outflow activity can be probed in numerous different regimes from radio to X-ray wavelengths. Recent discoveries have shown that it is not only solar mass stars that launch outflows during their formation but also the sub-stellar brown dwarfs. In this article what is currently known about jets from young stars is summarised, including an outline of why it is important to study jets. The second part of this article is dedicated to jets from young brown dwarfs. While only a small number of brown dwarf outflows have been investigated to date, interesting properties have been observed. Here observations of brown dwarf outflows are described and what is currently known of their properties compared to low mass protostellar outflows. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Liebner S.,Goethe University Frankfurt | Czupalla C.J.,Goethe University Frankfurt | Wolburg H.,University of Tubingen
International Journal of Developmental Biology | Year: 2011

Homeostasis of the central nervous system (CNS) microenvironment is essential for its normal function and is maintained by the blood-brain barrier (BBB). The BBB proper is made up of endothelial cells (ECs) interconnected by tight junctions (TJs) that reveal a unique morphology and biochemical composition of the body's vasculature. In this article, we focus on developmental aspects of the BBB and describe morphological as well as molecular special features of the neuro-vascular unit (NVU) involved in barrier induction. Recently, we and others identified the Wnt/b-catenin pathway as crucial for brain angiogenesis, TJ and BBB formation. Based on these findings we discuss other pathways and molecular interactions for BBB establishment and maintenance. At the morphological level, our concept favors a major role for polarized astrocytes (ACs) therein. Orthogonal arrays of particles (OAPs) that are the morphological correlate of the water channel protein aquaporin-4 (AQP4) are specifically formed in the membrane of the AC endfoot. The polarized AC endfoot and hence OAPs are dependent on agrin and dystroglycan, of which agrin is a developmentally regulated extracellular matrix (ECM) component. Understanding the mechanisms leading to BBB development will be key to the understanding of barrier maintenance that is crucial for, but frequently disturbed, in the diseased adult brain. © 2011 UBC Press.

Quinones are ubiquitously present in mammals and their environment. They are involved in physiologic functions such as electron transport but are also toxic compounds. In particular, quinone-quinol redox cycles may lead to oxidative stress, and arylating quinones have been demonstrated to activate endoplasmic reticulum (ER) stress. To detoxify quinones coordinately regulated Ah receptor and Nrf2 gene batteries evolved. Two pathways are emphasized: (i) glutathione S-transferases, and (ii) NAD(P)H:quinone oxidoreductases NQO1 and NQO2 acting together with UDP-glucuronosyltransferases and sulfotransferases. Coupling between these enzymes may prevent oxidative and ER stress in a tissue-dependent manner, as discussed using benzo[a]pyrene detoxification in enterocytes, catecholestrogen metabolism in breast tissue and endometrium, and aminochromes in neurones and astrocytes. Possible consequences of chronic ER stress such as apoptosis and inflammation as well as therapeutic possibilities of modulating Ah receptor and Nrf2 are discussed. In conclusion, tight coupling of Ah receptor- and Nrf2-regulated enzymes may prevent quinone-mediated oxidative and ER stress.© 2011 Elsevier Inc. All rights reserved.

Piras F.,University of Tubingen | Coull J.T.,French National Center for Scientific Research
PLoS ONE | Year: 2011

It is not yet known whether the scalar properties of explicit timing are also displayed by more implicit, predictive forms of timing. We investigated whether performance in both explicit and predictive timing tasks conformed to the two psychophysical properties of scalar timing: the Psychophysical law and Weber's law. Our explicit temporal generalization task required overt estimation of the duration of an empty interval bounded by visual markers, whereas our temporal expectancy task presented visual stimuli at temporally predictable intervals, which facilitated motor preparation thus speeding target detection. The Psychophysical Law and Weber's Law were modeled, respectively, by (1) the functional dependence between mean subjective time and real time (2) the linearity of the relationship between timing variability and duration. Results showed that performance for predictive, as well as explicit, timing conformed to both psychophysical properties of interval timing. Both tasks showed the same linear relationship between subjective and real time, demonstrating that the same representational mechanism is engaged whether it is transferred into an overt estimate of duration or used to optimise sensorimotor behavior. Moreover, variability increased with increasing duration during both tasks, consistent with a scalar representation of time in both predictive and explicit timing. However, timing variability was greater during predictive timing, at least for durations greater than 200 msec, and ascribable to temporal, rather than non-temporal, mechanisms engaged by the task. These results suggest that although the same internal representation of time was used in both tasks, its external manifestation varied as a function of temporal task goals. © 2011 Piras, Coull.

Expression profiles of human adult and fetal hepatic and intestinal UDP-glucuronosyltransferases (UGTs), information about their endo- and xenobiotic substrates, and their transcriptional regulation suggests regulatory circuits between some UGT substrates and ligands of their transcription factors. For examples: (i) bilirubin is solely conjugated by UGT1A1 and activates its transcription factors Ah receptor, PXR and CAR. (ii) Hepatotoxic lithocholic acid (LCA) is oxidized to hyodeoxycholic acid, the latter conjugated by UGT2B4 and UGT2B7. LCA is also an agonist of FXR and PPARα, which are controlling these UGTs. (iii) Similar feedback loops possibly exist between some eicosanoids, PPARα and UGTs. (iv) Regulatory circuits may also have evolved between dietary polyphenols, which are efficient substrates of UGTs and activators of the Ah receptor. Although many newly developed drugs are conjugated by promiscuous UGTs, the discussed regulatory circuits may provide hints to evolutionary important UGT substrates. © 2012 Elsevier Inc.

Schuster A.,Heinrich Heine University Dusseldorf | Haliburn C.,Data Management | Doring G.,University of Tubingen | Goldman M.H.,Forest Laboratories
Thorax | Year: 2013

Purpose To assess efficacy and safety of a new dry powder formulation of inhaled colistimethate sodium in patients with cystic fibrosis (CF) aged ≥6 years with chronic Pseudomonas aeruginosa lung infection. Study design and methods A prospective, centrally randomised, phase III, open-label study in patients with stable CF aged ≥6 years with chronic P aeruginosa lung infection. Patients were randomised to Colobreathe dry powder for inhalation (CDPI, one capsule containing colistimethate sodium 1 662 500 IU, twice daily) or three 28-day cycles with twice-daily 300 mg/5 ml tobramycin inhaler solution (TIS). Study duration was 24 weeks. Results 380 patients were randomised. After logarithmic transformation of data due to a non-normal distribution, adjusted mean difference between treatment groups (CDPI vs TIS) in change in forced expiratory volume in 1 s (FEV1% predicted) at week 24 was -0.98% (95% CI -2.74% to 0.86%) in the intentionto-treat population (n=373) and -0.56% (95% CI -2.71% to 1.70%) in the per protocol population (n=261). The proportion of colistin-resistant isolates in both groups was ≤1.1%. The number of adverse events was similar in both groups. Significantly more patients receiving CDPI rated their device as 'very easy or easy to use' (90.7% vs 53.9% respectively; p<0.001). Conclusion CDPI demonstrated efficacy by virtue of non-inferiority to TIS in lung function after 24 weeks of treatment. There was no emergence of resistance of P aeruginosa to colistin. Overall, CDPI was well tolerated.

The Early to Middle Miocene fossil locality Sandelzhausen has yielded 48 species of ectothermic vertebrates and thus represents one of the most diverse ectotherm faunas of Miocene age. Thirty-five taxa of fishes, amphibians and reptiles, including three new species: Pelobates fahlbuschi nov. sp. (Pelobatidae, the most abundant vertebrate), Tropidophorus bavaricus nov. sp. (Lygosominae) and Bavaricordylus molassicus nov. sp. (Cordylidae), are described. Three additional species are new, but are not named yet: Ranidae indet. nov. gen. et sp., Anguidae gen. indet. sp. nov. and Palaeoblanus sp. nov. (Amphisbaenidae). In order to reconstruct the palaeoenvironment and past hydrologic conditions, a new methodology (the tooth replacement method, TRM) is introduced, which allows for the detection of autochthonous components within freshwater fish taphocoenose. TRM is tested on 45 localities from the Upper Freshwater Molasse and gives reasonable results in agreement with other analytical approaches. It is therefore viewed as a reliable method to distinguish perennial from seasonal water conditions at the Sandelzhausen locality. Using the TRM it was demonstrated that the palaeohydrology of Sandelzhausen is characterized by a change from temporary water to permanent water conditions. During the period of temporary water conditions (units B to D1, lower part) the ecosystem was driven by seasonal inundations, and the remaining riparian pools have yielded no autochthonous fish population, but acted as spawning places for amphibians (amphibian pool). A mostly open habitat in the close vicinity, with sandy and non-groundwater-affected soils during the dry season, is suggested based on the absolute dominance of the spadefoot Pelobates fahlbuschi nov. sp. This ecosystem changed up-section (late part of unit D1 and during D2 and E) due to the establishment of permanent water conditions of riparian pond type, preserving an autochthonous Palaeocarassius/Channa fish population (fish pond). The reconstructed precipitation values suggest that the observed change in hydrologic conditions was probably driven by climate. The lower part of the section gives semi-arid/sub-humid values, with 571 mm mean annual precipitation (MAP), whereas the upper part yields sub-humid/humid values of 847 mm MAP. The increase in precipitation by about 280 mm was perhaps caused by a less seasonal precipitation regime with concomitant higher regional groundwater tables during units D2 and E. Based on the occurrence of several thermophilous reptile species, and in agreement with palaeobotanical and oxygen isotope data, the climate of Sandelzhausen is interpreted as subtropical with mean annual temperatures from 18°C to 20.8°C, mean cold month temperatures from 12.6°C to 13.3°C and mean warm month temperatures from 25.1°C to 28.1°C. © 2010 Springer-Verlag.

Karnath H.O.,University of Tubingen
Brain structure & function | Year: 2010

Normally, we are aware that our arms and legs belong to us and not to someone else. However, some stroke patients with hemiparesis/-plegia after right-sided stroke show a disturbed sensation of limb ownership and a disturbed self-awareness of actions and such patients with anosognosia for hemiparesis/plegia typically deny their paresis/-plegia and are convinced that their limbs function normally. They may experience their limb(s) as not belonging to them and may even attribute them to other persons. Modern lesion analyses techniques in such patients and recent neuroimaging results in healthy subjects suggest a prominent role of the right insula for our sense of limb ownership as well as for our feeling of being involved in a movement-our sense of agency. We thus hypothesize that the right insular cortex constitutes a central node of a network involved in human body scheme representation.

Reith J.,University of Konstanz | Mayer C.,University of Konstanz | Mayer C.,University of Tubingen
Applied Microbiology and Biotechnology | Year: 2011

Bacterial cells are protected by an exoskeleton, the stabilizing and shape-maintaining cell wall, consisting of the complex macromolecule peptidoglycan. In view of its function, it could be assumed that the cell wall is a static structure. In truth, however, it is steadily broken down by peptidoglycan-cleaving enzymes during cell growth. In this process, named cell wall turnover, in one generation up to half of the preexisting peptidoglycan of a bacterial cell is released from the wall. This would result in a massive loss of cell material, if turnover products were not be taken up and recovered. Indeed, in the Gram-negative model organism Escherichia coli, peptidoglycan recovery has been recognized as a complex pathway, named cell wall recycling. It involves about a dozen dedicated recycling enzymes that convey cell wall turnover products to peptidoglycan synthesis or energy pathways. Whether Gram-positive bacteria also recover their cell wall is currently questioned. Given the much larger portion of peptidoglycan in the cell wall of Gram-positive bacteria, however, recovery of the wall material would provide an even greater benefit in these organisms compared to Gram-negatives. Consistently, in many Gram-positives, orthologs of recycling enzymes were identified, indicating that the cell wall may also be recycled in these organisms. This mini-review provides a compilation of information about cell wall turnover and recycling in Gram-positive bacteria during cell growth and division, including recent findings relating to muropeptide recovery in Bacillus subtilis and Clostridium acetobutylicum from our group. Furthermore, the impact of cell wall turnover and recycling on biotechnological processes is discussed. © Springer-Verlag 2011.

Haring H.-U.,University of Tubingen | Merker L.,Diabetes und Nierenzentrum | Seewaldt-Becker E.,Boehringer Ingelheim | Weimer M.,Boehringer Ingelheim | And 3 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes. RESEARCHDESIGNANDMETHODSdPatients inadequately controlled on metformin and sulfonylurea (HbA1c ≥7 to ≤10%) were randomized and treated with once-daily empagliflozin 10 mg (n = 225), empagliflozin 25 mg (n = 216), or placebo (n = 225) for 24 weeks. The primary end point was change frombaseline inHbA1c atweek 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24. RESULTS-At week 24, adjusted mean (SE) changes from baseline in HbA1c were 20.17% (0.05) for placebo vs. 20.82% (0.05) and 20.77% (0.05) for empagliflozin 10 and 25 mg, respectively (both P < 0.001). Empagliflozin significantly reduced MDG, weight, and systolic (but not diastolic) blood pressure versus placebo. Adverse events were reported in 62.7, 67.9, and 64.1% of patients on placebo and empagliflozin 10 and 25 mg, respectively. Events consistent with urinary tract infection were reported in 8.0, 10.3, and 8.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 13.3, 18.0, and 17.5%, respectively; males: 2.7, 2.7, and 0%, respectively). Events consistent with genital infection were reported in 0.9, 2.7, and 2.3%of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 0.9, 4.5, and 3.9%, respectively; males: 0.9% in each group). CONCLUSIONS-Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin plus sulfonylurea improved glycemic control, weight, and systolic blood pressure and were well tolerated. © 2013 by the American Diabetes Association.

One of the key features of active perception is the ability to predict critical sensory events. Humans and animals can implicitly learn statistical regularities in the timing of events and use them to improve behavioral performance. Here, we used a signal detection approach to investigate whether such improvements in performance result from changes of perceptual sensitivity or rather from adjustments of a response criterion. In a regular sequence of briefly presented stimuli, human observers performed a noise-limited motion detection task by monitoring the stimulus stream for the appearance of a designated target direction. We manipulated target predictability through the hazard rate, which specifies the likelihood that a target is about to occur, given it has not occurred so far. Analyses of response accuracy revealed that improvements in performance could be accounted for by adjustments of the response criterion; a growing hazard rate was paralleled by an increasing tendency to report the presence of a target. In contrast, the hazard rate did not affect perceptual sensitivity. Consistent with previous research, we also found that reaction time decreases as the hazard rate grows. A simple rise-to-threshold model could well describe this decrease and attribute predictability effects to threshold adjustments rather than changes in information supply. We conclude that, even under conditions of full attention and constant perceptual sensitivity, behavioral performance can be optimized by dynamically adjusting the response criterion to meet ongoing changes in the likelihood of a target.

Giovanelli M.,University of Tubingen
Studies in History and Philosophy of Science Part B - Studies in History and Philosophy of Modern Physics | Year: 2013

The present paper attempts to show that a 1915 article by Erich Kretschmann must be credited not only for being the source of Einstein's point-coincidence, but also for having anticipated the main lines of the logical-empiricist interpretation of general relativity. Whereas Kretschmann was inspired by the work of Mach and Poincaré, Einstein inserted Kretschmann's point-coincidence parlance into the context of Ricci and Levi-Civita's absolute differential calculus. Kretschmann himself realized this and turned the point-coincidence argument against Einstein in his second and more famous 1918 paper. While Einstein had taken nothing from Kretschmann but the expression "point-coincidences", the logical empiricists, however, instinctively dragged along with it the entire apparatus of Kretschmann's conventionalism. Disappointingly, in their interpretation of general relativity, the logical empiricists unwittingly replicated some epistemological remarks Kretschmann had written before general relativity even existed. © 2012 Elsevier Ltd.

Diekelmann S.,University of Tubingen
Somnologie | Year: 2013

Sleep is well known to facilitate the consolidation of newly acquired memories. Although this effect has been extensively studied in the past two decades, there are still a number of issues that remain unresolved. In this article, some of the open questions in the field of sleep and memory research are discussed. Particularly, the psychological conditions that determine sleep-dependent memory consolidation as well as possible underlying physiological mechanisms are considered. With regard to the psychological conditions, it will be discussed to which extent the beneficial effect of sleep for memory consolidation depends on the type of learning task, type of retrieval test, releVance of the learning material for the individual, optimum temporal delay between learning and sleep, and amount of sleep. Concerning the physiological mechanisms, this article focuses on the role of different sleep stages and sleep parameters (e.g., sleep spindles, slow oscillations), as well as on the functional importance of memory reactivations ("neuronal replay") and synaptic downscaling during sleep. © 2013 Springer-Verlag Berlin Heidelberg.

Mervic L.,University of Tubingen | Mervic L.,University of Ljubljana
PLoS ONE | Year: 2012

Background: This study identified sex differences in progression of cutaneous melanoma. Methodology/Principal Findings: Of 7,338 patients who were diagnosed as an invasive primary CM without clinically detectable metastases from 1976 to 2008 at the University of Tuebingen in Germany, 1,078 developed subsequent metastases during follow up. The metastatic pathways were defined in these patients and analyzed using the Kaplan-Meier method. Multivariate survival analysis was performed using Cox modeling. In 18.7% of men and 29.2% of women (P<0.001) the first metastasis following diagnosis of primary tumor was locoregional as satellite/in-transit metastasis. The majority of men (54.0%) and women (47.6%, P = 0.035) exhibited direct regional lymph node metastasis. Direct distant metastasis from the stage of the primary tumor was observed in 27.3% of men and 23.2% of women (P = 0.13). Site of first metastasis was the most important prognostic factor of survival after recurrence in multivariate analysis (HR:1.3; 95% CI: 1.0-1.6 for metastasis to the regional lymph nodes vs. satellite/in-transit recurrence, and HR:5.5; 95% CI: 4.2-7.1 for distant metastasis vs. satellite/in-transit recurrence, P<0.001). Median time to distant metastasis was 40.5 months (IQR, 58.75) in women and 33 months (IQR, 44.25) in men (P = 0.002). Five-year survival after distant recurrence probability was 5.2% (95% CI: 1.4-2.5) for men compared with 15.3% (95% CI: 11.1-19.5; P = 0.008) for women. Conclusions/Significance: Both, the pattern of metastatic spread with more locoregional metastasis in women, and the time course with retracted metastasis in women contributed to the more favorable outcome of women. Furthermore, the total rate of metastasis is increased in men. Interestingly, there is also a much more favorable long term survival of women after development of distant metastasis. It remains a matter of debate and of future research, whether hormonal or immunologic factors may be responsible for these sex differences. © 2012 Liljana Mervic.

Rorden C.,Georgia Institute of Technology | Karnath H.-O.,Georgia Institute of Technology | Karnath H.-O.,University of Tubingen
Neuropsychologia | Year: 2010

Cancellation tasks are popular clinical and scientific tools for identifying spatial neglect, with neglect patients tending to miss targets on the contralesional side of the test. However, methods for analysis are not well established. Indeed, these tests are often used as a binary classifier to simply identify the presence or absence of spatial neglect, even though it is clear that there is a spectrum of disability on these tasks. We suggest that the Center of Cancellation (CoC) provides an intuitive, continuous and robust measure of neglect severity. First employed by Binder and colleagues [. Archives of Neurology, 49, 1187-1194 (1992)], its use has not been replicated since. Our aim was to ease deployment of this measure through validation, development of software and focused exposition. To validate this index, we evaluated a group of 110 individuals with right-hemisphere injury. For two different cancellation tasks (the Bells Test and the Letter Cancellation Task) we predicted spatial neglect (as defined by independent measures) using the new CoC index. Examining each individual's performance on a single cancellation task, we were able to correctly determine with better than 98% accuracy whether three tests with binary classifiers would define them as having spatial neglect. Specifically, an acute CoC score greater than 0.081 on the Bells Test or 0.083 on the Letter Cancellation Task turned out to indicate neglect behavior after a right-hemisphere brain lesion. Finally, we provide free software allowing other groups not only to rapidly analyze new but also previously existing (paper-and-pencil based) datasets using this measure. © 2010 Elsevier Ltd.

Hairer E.,University of Geneva | Lubich C.,University of Tubingen
Archive for Rational Mechanics and Analysis | Year: 2012

This paper presents a rigorous study, for Fermi-Pasta-Ulam (FPU) chains with large particle numbers, of the formation of a packet of modes with geometrically decaying harmonic energies from an initially excited single low-frequency mode and the metastability of this packet over longer time scales. The analysis uses modulated Fourier expansions in time of solutions to the FPU system, and exploits the existence of almost-invariant energies in the modulation system. The results and techniques apply to the FPU α- and β-models as well as to higher-order nonlinearities. They are valid in the regime of scaling between particle number and total energy in which the FPU system can be viewed as a perturbation to a linear system, considered over time scales that go far beyond standard perturbation theory. Weak non-resonance estimates for the almost-resonant frequencies determine the time scales that can be covered by this analysis. © 2012 Springer-Verlag.

Meule A.,University of Wurzburg | Kubler A.,University of Wurzburg | Kubler A.,University of Tubingen
Eating Behaviors | Year: 2012

Craving for a particular substance is an essential characteristic of addictive behavior. Increasing evidence suggests that food cravings and excessive food consumption could similarly be due to addictive processes. Recently, the Yale Food Addiction Scale (YFAS) was introduced for identifying individuals with addictive eating patterns. We conducted an online study (n= 616, 75.8% female) in which participants filled out the YFAS and the Food Cravings Questionnaire- Trait (FCQ-T). Participants diagnosed as being addicted to food using the YFAS had higher scores on all food craving subscales except for anticipation of positive reinforcement that may result from eating. In a subsequent regression analysis, all food craving subscales positively predicted food addiction symptoms while positive reinforcement negatively predicted food addiction symptoms. Similar to other addictive behaviors, results indicate that individuals with addictive eating patterns experience more food cravings, but concurrently do not expect a positive reinforcement through eating. © 2012 Elsevier Ltd.

Arteriovenous malformations (AVMs) proximal to motor cortical areas or motor projection systems are challenging to manage because of the risk of severe sensory and motor impairment. Surgical indication in these cases therefore remains controversial. To propose a standardized approach for centrally situated AVMs based on functional imaging and intraoperative electrophysiological evaluation. We conducted a retrospective analysis of 15 patients who underwent surgical treatment for AVMs in motor cortical areas or proximal to motor projections. Preoperative assessment included functional magnetic resonance and 3-dimensional tractography. Operations were performed under continuous electrophysiological monitoring aided by direct brain stimulation. We identified critical bloody supply to the motor areas by temporary occluding the feeding vessels under electrophysiological monitoring. Clinical outcome was evaluated with the modified Rankin Scale. Total resection was achieved in 12 cases, whereas electrophysiology limited total extirpation in 3 cases. A significant reduction of motor evoked potentials by up to 15% of the initial values was associated with good recovery of motor function; in contrast, the disappearance of potentials correlated with long-term impairment. The mean follow-up time was 13 months, and clinical assessments revealed overall functional improvement (P < .05). After surgery, 11 patients were asymptomatic or presented with only minor neurological deficits. Surgical resection of AVMs in eloquent motor areas can be considered a safe option for selected cases when performed in conjunction with a detailed functional assessment. Possible selection criteria for surgical treatment are discussed in light of the presented clinical data.

Zanger P.,University of Tubingen
Wiener Klinische Wochenschrift | Year: 2010

Staphylococcus aureus is a frequent cause of purulent skin infections in travellers returning from the tropics and subtropics. Th is review gives an account of the current knowledge on travel-related, S. aureus positive skin infections with a focus on recent fi ndings on both bacterial pathogenicity and mechanisms of innate defence. In particular, the potential role of community-acquired methicillin-resistance, Panton-Valentine leukocidin as well as antimicrobial peptides in the evolution of this type of infection are discussed. Moreover, conflicting fi ndings for a possible association of travel and migration with the global emergence of community-acquired methicillin-resistant S. aureus infections are summarised. Th is review highlights areas of uncertainty that require further investigation. © Springer-Verlag 2010.

A preliminary description of a new placoderm assemblage from the upper Frasnian of Morocco shows close similarity to the Bad Wildungen locality in Germany, with the arthrodire taxa Enseosteus, Rhinosteus, Walterosteus, Brachydeirus, Oxyosteus, Brachyosteus, Erromenosteus and Aspidichthys in common. Both horizons are from the late Frasnian, conodont Zone 13 (bogartensis). The North African assemblage is probably slightly younger, in between the lower and upper part of this Zone, the Upper rhenana to linguiformis Zone. Southern Morocco was located on the northern shelf of Gondwana and Bad Wildungen on the southern shelf of Laurussia during the Upper Devonian. The analysis of five late Frasnian localities is in conflict with the palaeogeographical model from the palaeomagnetic data, indicating a large ocean separating both continents. No palaeobiogeographical barrier to the placoderms was present between these continents, supporting an alternative hypothesis, primarily based on palaeontological data with a small ocean separating Gondwana and Laurussia and a connection in the Late Devonian. © 2009 Elsevier Ltd and Nanjing Institute of Geology and Palaeontology, CAS.

Evans M.E.,Friedrich - Alexander - University, Erlangen - Nuremberg | Roth R.,University of Tubingen
Physical Review Letters | Year: 2014

The stratum corneum, the outer layer of mammalian skin, provides a remarkable barrier to the external environment, yet it has highly variable permeability properties where it actively mediates between inside and out. On prolonged exposure to water, swelling of the corneocytes (skin cells composed of keratin intermediate filaments) is the key process by which the stratum corneum controls permeability and mechanics. As for many biological systems with intricate function, the mesoscale geometry is optimized to provide functionality from basic physical principles. Here we show that a key mechanism of corneocyte swelling is the interplay of mesoscale geometry and thermodynamics: given helical tubes with woven geometry equivalent to the keratin intermediate filament arrangement, the balance of solvation free energy and elasticity induces swelling of the system, importantly with complete reversibility. Our result remarkably replicates macroscopic experimental data of native through to fully hydrated corneocytes. This finding not only highlights the importance of patterns and morphology in nature but also gives valuable insight into the functionality of skin. © 2014 American Physical Society.

Passamonti A.,National institute for astrophysics | Lander S.K.,University of Tubingen
Monthly Notices of the Royal Astronomical Society | Year: 2014

We study the time evolution of axisymmetric oscillations of superfluid magnetars with a poloidal magnetic field and an elastic crust, working in Newtonian gravity. Extending earlier models, we study the effects of composition gradients and entrainment on the magneto-elastic wave spectrum and on the potential identification of the observed quasi-periodic oscillations (QPOs). We use two-fluid polytropic equations of state to construct our stellar models, which mimic realistic composition gradient configurations. The basic features of the axial axisymmetric spectrum of normal fluid stars are reproduced by our results and in addition we find several magneto-elastic waves with a mixed character. In the core, these oscillations mimic the shear mode pattern of the crust as a result of the strong dynamical coupling between these two regions. Incorporating the most recent entrainment configurations in our models, we find that they have a double effect on the spectrum: the magnetic oscillations of the core have a frequency enhancement, while the mixed magneto-elastic waves originating in the crust are moved towards the frequencies of the single-fluid case. The distribution of lower frequency magneto-elastic oscillations for our models is qualitatively similar to the observed magnetar QPOs with ν < 155 Hz. In particular, some of these QPOs could represent mixed magneto-elastic oscillations with frequencies not greatly different from the crustal modes of an unmagnetized star. We find that many QPOs could even be accounted for using a model with a relatively weak polar field of Bp ≃ 3 × 1014 G, because of the superfluid enhancement of magnetic oscillations. Finally, we discuss the possible identification of 625 and 1837 Hz QPOs either with non-axisymmetric modes or with high-frequency axisymmetric QPOs excited by crustal mode overtones. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.

Salt A.N.,University of Washington | Plontke S.K.,University of Tubingen
Otolaryngologic Clinics of North America | Year: 2010

It is well established that endolymphatic hydrops plays a role in Ménière disease, even though the precise role is not fully understood and the presence of hydrops in the ear does not always result in symptoms of the disease. It nevertheless follows that a scientific understanding of how hydrops arises, how it affects the function of the ear, and how it can be manipulated or reversed could contribute to the development of effective treatments for the disease. Measurements in animal models in which endolymphatic hydrops has been induced have given numerous insights into the relationships between hydrops and other pathologic and electrophysiological changes, and how these changes influence the function of the ear. The prominent role of the endolymphatic sac in endolymph volume regulation, and the cascade of histopathological and electrophysiological changes that are associated with chronic endolymphatic hydrops, have now been established. An increasing number of models are now available that allow specific aspects of the interrelationships to be studied. The yclical nature of Ménière symptoms gives hope that treatments can be developed to maintain the ear in permanent state of remission, possibly by controlling endolymphatic hydrops, thereby avoiding the rogressive damage and secondary pathologic changes that may also contribute to the patient's symptoms. © 2010 Elsevier Ltd.

Gallwitz B.,University of Tubingen
Therapeutic Advances in Endocrinology and Metabolism | Year: 2013

Dipeptidyl-peptidase-IV (DPP-4) inhibitors have become an important orally active drug class for the treatment of type 2 diabetes as second-line therapy after metformin failure or as monotherapy or combination therapy with other drugs when metformin is not tolerated or contraindicated. DPP-4 inhibitors act mainly by increasing endogenous incretin hormone concentrations. They stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner with a significantly lower risk for hypoglycaemia than sulfonylureas. Furthermore, DPP-4 inhibitors are weight neutral. Linagliptin is a DPP-4 inhibitor that is eliminated by a hepatobiliary route, whereas the other DPP-4 inhibitors available today show a renal elimination. Therefore, it can be used in normal kidney function as well as in all stages of chronic kidney disease to stage 5 (glomerular filtration rate <15 ml/min/1.73 m2) without dose adjustments. Linagliptin was noninferior to metformin and sulfonylureas in clinical studies. In recent studies, it showed a superior safety profile over sulfonylurea treatment regarding hypoglycaemia and weight gain. More patients reached an HbA1c <7% without hypoglycaemia and weight gain with linagliptin compared with glimepiride. The safety profile with respect to a composite cardiovascular endpoint and stroke was also favourable for linagliptin, most likely due to a higher incidence of hypoglycaemia associated with glimepiride therapy and titration. This review gives an overview on the efficacy and safety of linagliptin in comparison with other antidiabetic drugs in type 2 diabetes patients with renal and cardiovascular risk factors as well as an outlook on the perspective for linagliptin in this patient population in the future. © The Author(s), 2013.

Wilhelm H.,University of Tubingen
Handbook of Clinical Neurology | Year: 2011

Pupil size is determined by the interaction of the parasympathetic and the sympathetic nervous system. The parasympathetic system conducts the light reaction with its major center in the dorsal midbrain. The sympathetic nervous system acts either directly on the dilator muscle (peripherally) or centrally by inhibiting the Edinger-Westphal nucleus. Psychosensory reactions are transmitted via the sympathetic system.The afferent input of the light reflex system in humans is characteristically wired, allowing a detailed analysis of a lesion of the afferent input. Even in humans a subgroup of ganglion cells containing melansopsin plays an important role as a light sensor for the pupillary system.To diagnose normal pupillary function, pupils need to be isocoric and react bilaterally equally to light. Anisocoria indicates a problem of the efferent pupillary pathway.Pupillary disorders may involve the afferent pathways (relative afferent pupillary defect) or the efferent pathways. Physiological anisocoria is a harmless condition that has to be distinguished from Horner's syndrome. In this case pharmacological testing with cocaine eye-drops is helpful. Disorders of the parasympathetic system will impair the light response. They include dorsal midbrain syndrome, third-nerve palsy, and tonic pupil. Tonic pupils are mainly idiopathic and do not need imaging. Disorders of the iris, including application of cholinergic agents, need also to be considered in impaired pupillary light reaction. © 2011 Elsevier B.V.

Lang F.,University of Tubingen | Stournaras C.,University of Crete
Hormones | Year: 2013

Serum-and-glucocorticoid-inducible-kinase-1 (SGK1) is under regulation of several hormones, mediators and cell stressors. More specifically, SGK1 expression is particularly sensitive to glucocorticoids, mineralocorticoids, and TGFβ. Moreover, SGK1 expression is exquisitely sensitive to hypertonicity, hyperglycemia, and ischemia. SGK1 is activated by insulin and growth factors via phosphatidylinositol-3-kinase, 3-phosphoinositide dependent-kinase PDK1, and mTOR. SGK1 up-regulates the Na+/K+-ATPase, a variety of carriers (e.g. NCC, NKCC, NHE1, NHE3, SGLT1, several amino acid transporters) and many ion channels (e.g. ENaC, SCN5A, TRPV4-6, Orai1/STIM1, ROMK, KCNE1/KCNQ1, GluR6, CFTR). SGK1 further up-regulates a number of enzymes (e.g. glycogen-synthase-kinase-3, ubiquitin-ligase Nedd4-2), and transcription factors (e.g. forkhead-transcription-factor FOXO3a, β-catenin, nuclear-factor-kappa-B NFκB). SGK1 sensitive functions contribute to regulation of epithelial transport, excitability, degranulation, matrix protein deposition, coagulation, platelet aggregation, migration, cell proliferation, and apoptosis. Apparently, SGK1 is not required for housekeeping functions, as the phenotype of SGK1 knockout mice is mild. However, excessive SGK1 expression and activity participates in the pathophysiology of several disorders, including hypertension, obesity, diabetes, thrombosis, stroke, inflammation, autoimmune disease, fibrosis, and tumor growth. A SGK1 gene variant (prevalence ~3-5% prevalence in Caucasians, ~10% in Africans) predisposes to hypertension, stroke, obesity, and type 2 diabetes. Moreover, excessive salt intake and/or excessive release of glucocorticoids, mineralocorticoids, and TGFβ up-regulates SGK1 expression thus predisposing to SGK1-related diseases.

Li Y.-L.,University of Hong Kong | Konhauser K.O.,University of Alberta | Kappler A.,University of Tubingen | Hao X.-L.,University of Hong Kong
Earth and Planetary Science Letters | Year: 2013

During the deposition of banded iron formation (BIF), the downward flux of ferric oxyhydroxides and phytoplankton biomass should have facilitated Fe(III) reduction during burial, with the end product being ferrous iron-containing minerals including magnetite. Although earlier studies have attempted to quantify the significance of this pathway based on models of the ancient Fe cycle, the only direct evidences of a biological role in magnetite formation in BIF are their iron isotope compositions and unique crystallography which are reminiscent of biologically-generated magnetite. However, the biogenesis hypothesis lacks an explanation as to why modern biogenic magnetite crystals are generally a few hundred nm or smaller in size, yet the magnetite crystals in BIF are mostly tens of micrometers or larger in size. In this study, we demonstrate that biogenic magnetite crystals can grow in size upon reaction between oxyhydroxide and microbial biomass after compression and heating to 1. kbar and 150. °C, respectively. The magnetite crystals previously produced by Thermoanaerobacter spp. TOR39 reach sizes in excess of 700. nm after the P-T experiments, while new magnetite grains >400. nm formed from the superparamagnetic magnetite-dominated end product of Shewanella sp. culture. This study indicates that the large magnetite crystals observed in BIF can be derived through a three-stage sequence, beginning with dissimilatory iron reduction of an initial ferric iron-rich sediment coupled to the oxidation of dead phytoplankton biomass, followed by magnetite crystal aging, and ultimately pressure-temperature induced abiotic alteration of the biogenic magnetite during metamorphism. © 2012 Elsevier B.V.

Akbayram K.,Technical University of Istanbul | Okay A.I.,Technical University of Istanbul | Satir M.,University of Tubingen
Journal of Geodynamics | Year: 2013

The Intra-Pontide suture is the boundary between the İstanbul and Sakarya terranes in northwest Turkey. We provide new isotopic and stratigraphical data from the Intra-Pontide suture zone, which indicate Early Cretaceous collision between the Sakarya and İstanbul terranes. These two terranes along with the Strandja Massif make up the Pontides. Metamorphic units of the Intra-Pontide suture zone are best exposed in the Armutlu Peninsula. In the eastern part of the Armutlu Peninsula, three metamorphic units crop out forming an eastward dipping thrust stack. At the base of the thrust stack there is a metaclastic-marble sequence, which is tectonically overlain by a Cretaceous subduction-accretion complex, farther up in the thrust stack there is a high-grade metamorphic unit, which represents the Proterozoic basement of the İstanbul Zone. New clastic zircon ages from the metaclastic-marble sequence indicate that deposition of the sandstones must be later than Permian (∼264. Ma) possibly during Triassic. Similar Triassic metasediments are also reported in Strandja Massif. We interpret that these metasediments were deposited during Triassic along the rift flanks leading to the opening of the Intra-Pontide Ocean, which suggest a possible Early Triassic opening for the Intra-Pontide Ocean. Our new Rb-Sr mica and Sm-Nd garnet ages dates the regional metamorphism between Late Jurassic-Early Cretaceous (158-111. Ma) along the Intra-Pontide suture zone, similar ages are also reported in the Strandja Massif. The metamorphic rocks of the Intra-Pontide suture are unconformably overlain by Campanian-Ypresian clastics. The collision between the İstanbul and Sakarya-Strandja terranes has occurred during Early Cretaceous and the Proterozoic basement of İstanbul terrane was reheated during this collision. © 2012 Elsevier Ltd.

Seyrich J.,University of Tubingen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

In this work, we present the hitherto most efficient and accurate method for the numerical integration of post-Newtonian equations of motion. We first transform the Poisson system as given by the post-Newtonian approximation to canonically symplectic form. Then we apply Gauss Runge-Kutta schemes to numerically integrate the resulting equations. This yields a convenient method for the structure preserving long-time integration of post-Newtonian equations of motion. In extensive numerical experiments, this approach turns out to be faster and more accurate (i) than previously proposed structure preserving splitting schemes and (ii) than standard explicit Runge-Kutta methods. We also show our approach to be appropriate for simulations on transitional precession. © 2013 American Physical Society.

Dora B.,Budapest University of Technology and Economics | Pollmann F.,Max Planck Institute For Physik Komplexer Systeme | Fortagh J.,University of Tubingen | Zarand G.,Budapest University of Technology and Economics
Physical Review Letters | Year: 2013

We investigate the many-body generalization of the orthogonality catastrophe by studying the generalized Loschmidt echo of Luttinger liquids (LLs) after a global change of interaction. It decays exponentially with system size and exhibits universal behavior: the steady state exponent after quenching back and forth n times between 2 LLs (bang-bang protocol) is 2n times bigger than that of the adiabatic overlap and depends only on the initial and final LL parameters. These are corroborated numerically by matrix-product state based methods of the XXZ Heisenberg model. An experimental setup consisting of a hybrid system containing cold atoms and a flux qubit coupled to a Feshbach resonance is proposed to measure the Loschmidt echo using rf spectroscopy or Ramsey interferometry. © 2013 American Physical Society.

Yazadjiev S.S.,Sofia University | Yazadjiev S.S.,University of Tubingen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

In the present paper, we construct a new solution to the Einstein-Maxwell-dilaton gravity equations describing electrically charged dilaton black holes immersed in a strong external magnetic field, and we study its properties. The black holes described by the solution are rotating but with zero total angular momentum and possess an ergoregion confined in a neighborhood of the horizon. Our results also show that the external magnetic field does not affect the black hole thermodynamics. © 2013 American Physical Society.

Passamonti A.,University of Tubingen | Passamonti A.,University of Southampton | Andersson N.,University of Southampton
Monthly Notices of the Royal Astronomical Society | Year: 2012

We study the effects of an elastic crust on the oscillation spectrum of superfluid neutron stars. Within the two-fluid formalism, we consider Newtonian stellar models that include the relevant constituents of a mature neutron star. The core is formed by a mixture of superfluid neutrons and a conglomerate of charged particles, while the inner crust is described by a lattice of nuclei permeated by superfluid neutrons. We linearize the Poisson and the conservation equations of non-rotating superfluid stars and study the effects of elasticity, entrainment and composition stratification on the shear and acoustic modes. In both the core and the crust, the entrainment is derived from recent results for the nucleon effective mass. Solving the perturbation equations as an eigenvalue problem, we find that the presence of superfluid neutrons in the crust and their large effective mass may have significant impact on the star's oscillation spectrum. © 2011 The Authors Monthly Notices of the Royal Astronomical Society © 2011 RAS.

Lander S.K.,University of Southampton | Lander S.K.,Max Planck Institute For Gravitationsphysik | Andersson N.,University of Southampton | Glampedakis K.,University of Tubingen
Monthly Notices of the Royal Astronomical Society | Year: 2012

We construct two-fluid equilibrium configurations for neutron stars (NSs) with magnetic fields, using a self-consistent and non-linear numerical approach. The two-fluid approach - likely to be valid for large regions of all but the youngest NSs - provides us with a straightforward way to introduce stratification and allows for more realistic models than the ubiquitous barotropic assumption. In all our models, the neutrons are modelled as a superfluid, whilst for the protons we consider two cases: one where they are a normal fluid and another where they form a type II superconductor. We consider a variety of field configurations in the normal-proton case and purely toroidal fields in the superconducting case. We find that stratification allows for a stronger toroidal component in mixed-field configurations, though the poloidal component remains the largest in all our models. We provide quantitative results for magnetic ellipticities of NSs, both in the normal- and superconducting-proton cases. © 2011 The Authors Monthly Notices of the Royal Astronomical Society © 2011 RAS.

Pfister H.,University of Tubingen
Classical and Quantum Gravity | Year: 2011

In comparison to previous existence proofs for static and spherically symmetric perfect fluid stars in general relativity the new proof applies to a more general class of equations of state. In the star's interior we allow for piecewise Lipschitz continuous functions, including in this way the physically important case of phase transitions. Near the star's surface we allow for even more general functions, thereby including a large class of polytropic equations of state. Furthermore, the proof technique proceeds along standard techniques of functional analysis (Banach's fixed point theorem), and therefore applies in a similar manner to static stars in Newtonian gravity, and perhaps to rotating Newtonian and Einsteinian stars. In detail, the Einstein field equations for static perfect fluid stars are transformed to a system of coupled nonlinear integral equations being valid equally in the matter region and in the vacuum exterior. These integral equations are interpreted as a mapping in a Banach space. With the standard iteration technique, beginning with appropriate start functions, it is proven that the mapping has a unique fixed point, and that the solutions have appropriate regularity properties determined by the properties of the equation of state. The introduction gives an overview of earlier work on such systems, on the question of sphericity of static fluid stars, and on possible extensions of the above methods to rotating Newtonian and Einsteinian stars. An outlook addresses the question whether our proof method may be extensible to piecewise Hölder continuous equations of state. © 2011 IOP Publishing Ltd.

Witte M.,University of Tubingen
Journal of Neurophysiology | Year: 2011

How the brain orchestrates the musculoskeletal system to produce complex three-dimensional movements is still poorly understood. Despite first promising results in brain-machine interfaces that translate cortical activity to control output, there is an ongoing debate about which brain signals provide richest information related to movement planning and execution. Novel results by Bansal and colleagues (2011) now suggest that neuronal spiking and local field potentials jointly encode kinematics during skilled reach and grasp movements. © 2011 by the American Physiological Society.

Jansen R.-P.,University of Tubingen | Jansen R.-P.,Helmholtz Center for Environmental Research | Jansen R.-P.,Heinrich Heine University Dusseldorf
Trends in genetics : TIG | Year: 2014

Active transport and local translation of mRNAs ensure the appropriate spatial organization of proteins within cells. Recent work has shown that this process is intricately connected to membrane trafficking. Here, we focus on new findings obtained in fungal model systems. Important highlights are that RNA-binding proteins recognize cargo mRNA synergistically and that mRNAs are co-transported with membranous compartments such as the endoplasmic reticulum (ER) and endosomes. We further discuss a novel concept of endosome-coupled translation that loads shuttling endosomes with septin cargo, a process important for correct septin filamentation. Interestingly, evidence is accumulating that RNA and membrane trafficking are also tightly interwoven in higher eukaryotes, suggesting that this phenomenon is a common theme and not an exception restricted to fungi. Copyright © 2014 Elsevier Ltd. All rights reserved.

Mueck A.O.,University of Tubingen | Sitruk-Ware R.,Rockefeller University
Steroids | Year: 2011

Nomegestrol acetate (NOMAC) is a potent, highly selective progestogen, which is structurally similar to 19-norprogesterone and characterized as a full agonist at the progesterone receptor, with no or minimal binding to other steroid receptors, including the androgen and glucocorticoid receptors. In animal models, NOMAC demonstrated moderate antiandrogenic activity and strong antiestrogenic activity. In clinical studies, the progestogen was associated with effective suppression of gonadotropic activity and ovulation in premenopausal women, and a neutral impact on hemostasis, lipids, and carbohydrate metabolism. In normal and cancerous human breast tissue, NOMAC has shown favorable effects on estrogen metabolism, and in human breast cancer cell lines in vitro, it does not stimulate cell proliferation. The pharmacologic profile of NOMAC suggested that it would be well suited for combination with a physiologic estrogen in a combined oral contraceptive (COC), with the aim of achieving effective contraception with good cycle control and a favorable safety profile. A monophasic COC containing NOMAC 2.5 mg and 17β-estradiol (E2) 1.5 mg, administered in a 24/4-day regimen, is currently under clinical investigation. In a phase III study, NOMAC/E2 provided consistent and robust ovulation inhibition, with contraceptive effects that compared favorably with those of drospirenone 3 mg/ethinyl estradiol (EE) 30 μg. Investigators for a second phase III study reported less overall impact with NOMAC/E2 on hemostatic, lipid, inflammatory, and carbohydrate metabolism parameters than with levonorgestrel 150 μg/EE 30 μg. These clinical findings are promising; however, full publication of results from the pivotal phase III trials of NOMAC/E2 is pending. © 2011 Elsevier Inc. All rights reserved.

Schlegel M.,University of Tubingen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

The single-spin asymmetry of unpolarized leptons scattering deep-inelastically off transversely polarized nucleons is studied in a partonic picture within a collinear twist-3 framework. Since this observable is generated by multiphoton exchanges between a lepton and nucleon a partonic description of the asymmetry contains essential elements of a full next-to-leading order calculation for single-spin asymmetries in perturbative quantum chromodynamics. In particular, it is shown how nontrivial cancellations between kinematical and dynamical twist-3 contributions lead to a well-behaved and finite formula. This final result can be expressed in terms of multipartonic quark-gluon and quark-photon correlation functions. Hence, a measurement of the transverse target single-spin asymmetry may provide new constraints on these multipartonic correlations. © 2013 American Physical Society.

Schindler A.,University of Tubingen
Cerebral cortex (New York, N.Y. : 1991) | Year: 2013

The perception of a melody is invariant to the absolute properties of its constituting notes, but depends on the relation between them-the melody's relative pitch profile. In fact, a melody's "Gestalt" is recognized regardless of the instrument or key used to play it. Pitch processing in general is assumed to occur at the level of the auditory cortex. However, it is unknown whether early auditory regions are able to encode pitch sequences integrated over time (i.e., melodies) and whether the resulting representations are invariant to specific keys. Here, we presented participants different melodies composed of the same 4 harmonic pitches during functional magnetic resonance imaging recordings. Additionally, we played the same melodies transposed in different keys and on different instruments. We found that melodies were invariantly represented by their blood oxygen level-dependent activation patterns in primary and secondary auditory cortices across instruments, and also across keys. Our findings extend common hierarchical models of auditory processing by showing that melodies are encoded independent of absolute pitch and based on their relative pitch profile as early as the primary auditory cortex.

Genetically determined variation in the expression of innate defense molecules may explain differences in the propensity to be colonized with Staphylococcus aureus. We determined S. aureus nasal carriage in 603 volunteers; analyzed polymorphisms in the DEFB1 promoter at positions -52 G>A (rs1799946), -44 C>G (rs1800972), and -20 G>A (rs11362); and measured the content of human β-defensin 1 (hBD-1) and hBD-3 messenger RNA (mRNA) in 192 samples of healthy and experimentally wounded human skin. Compared with GGG at the positions -52/-44/-20, the ACG haplotype was more common among persistent S. aureus nasal carriers (odds ratio, 1.93; 95% confidence interval [CI], 1.2-3.1; P = .006) and was associated with reduced expression of hBD-1 (GGG>ACG>GCA; P < .001) and hBD-3 (GGG>GCA>ACG; P = .04) in skin when measured 72 hours after wounding. Furthermore, a 50% decrease in hBD-1 and hBD-3 mRNA expression in wounded skin increased the odds of persistent carriage by 1.45 (95% CI, .93-2.26; P = .1) and 1.48 (95% CI, 1.01-2.17; P = .04), respectively. Adjustment for known risk factors of persistent S. aureus carriage did not substantially change the associations of both DEFB1 haplotypes and β-defensin expression with S. aureus colonization. DEFB1 polymorphisms may promote persistent S. aureus colonization by altering β-defensin expression in keratinocytes of human skin.

Stingl K.,University of Tubingen
Proceedings. Biological sciences / The Royal Society | Year: 2013

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm(2) chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s(-1)), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037° or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant's power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.

Meru F.,University of Exeter | Meru F.,University of Tubingen | Bate M.R.,University of Exeter
Monthly Notices of the Royal Astronomical Society: Letters | Year: 2011

We carry out a resolution study on the fragmentation boundary of self-gravitating discs. We perform three-dimensional Smoothed Particle Hydrodynamics simulations of discs to determine whether the critical value of the cooling time-scale in units of the orbital time-scale, β crit, converges with increasing resolution. Using particle numbers ranging from 31 250 to 16 million (the highest resolution simulations to date) we do not find convergence. Instead, fragmentation occurs for longer cooling time-scales as the resolution is increased. These results suggest that at the very least, the critical value of the cooling time-scale is longer than previously thought. However, the absence of convergence also raises the question of whether or not a critical value exists. In light of these results, we caution against using cooling time-scale or gravitational stress arguments to deduce whether gravitational instability may or may not have been the formation mechanism for observed planetary systems. © 2010 The Authors Monthly Notices of the Royal Astronomical Society © 2010 RAS.

Besides mediating primary hemostasis and thrombosis, platelets play a critical role in tissue repair and regeneration. They regulate fundamental mechanisms involved in the healing process including cellular migration, proliferation, and angiogenesis. Control of apoptosis/cell survival and interaction with progenitor cells, which are clinically relevant but poorly understood aspects of platelets in tissue repair, will be highlighted in this review. Gaining deeper insight into the less well-characterized molecular mechanisms is necessary to develop new therapeutic platelet-based options.

Braun V.,Max Planck Institute for Developmental Biology | Hantke K.,University of Tubingen
Current Opinion in Chemical Biology | Year: 2011

Bacteria are confronted with a low availability of iron owing to its insolubility in the Fe3+ form or its being bound to host proteins. The bacteria cope with the iron deficiency by using host heme or siderophores synthesized by themselves or other microbes. In contrast to most other nutrients, iron compounds are tightly bound to proteins at the cell surfaces, from which they are further translocated by highly specific proteins across the cell wall of gram-positive bacteria and the outer membrane of gram-negative bacteria. Once heme and iron siderophores arrive at the cytoplasmic membrane, they are taken up across the cytoplasmic membrane by ABC transporters. Here we present an outline of bacterial heme and iron siderophore transport exemplified by a few selected cases in which recent progress in the understanding of the transport mechanisms has been achieved. © 2011 Elsevier Ltd.

Meyer H.-J.,University of Tubingen
Dalton Transactions | Year: 2010

Solid state metathesis reactions can be used in the syntheses of inorganic solids and for strategic design of novel, eventually thermally labile materials. An explorative study of solid state metathesis reactions is presented for a number of examples, including syntheses of nitridoborates, carbodiimides, tetracyanoborates, tetracyanamidosilicates, carbon-nitride materials, and a number of other exciting compounds. This unique type of reaction is very efficient because it uses the intrinsic energy of reaction partners being involved. Desired compositions are achieved by appropriate starting materials and their relative amounts being combined into a solid state metathesis reaction. Reactions can be controlled through the heating-up procedure and by using a reactive flux, which may lower the ignition temperature of a reaction mixture and promote crystal growth of products. © 2010 The Royal Society of Chemistry.

Muhlenbernd R.,University of Tubingen
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2014

Lewis [L1] invented signaling games to show that semantic meaning conventions can arise simply from regularities in communicative behavior. The behavioral implementation of such conventions are so-called signaling systems. Previous research addressed the emergence of signaling systems by combining signaling games with learning dynamics, and not uncommonly researchers examined the circumstances preventing the emergence of signaling systems. It has been shown that by increasing the number of states, messages and actions for a signaling game, the emergence of signaling becomes increasingly improbable. This paper contributes to the question of how the invention of new messages and extinction of unused messages would change these outcomes. Our results reveal that this innovation mechanism does in fact support the emergence of signaling systems. Furthermore, we analyze circumstances that lead to stable communication structure in large spatial population structures of interacting players. © 2014 Springer-Verlag Berlin Heidelberg.

20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8+ T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4+ T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.Leukemia advance online publication, 29 August 2014; doi:10.1038/leu.2014.233.

Gallwitz B.,University of Tubingen
Drug Safety | Year: 2010

Exenatide is the first incretin mimetic, introduced into type 2 diabetes mellitus therapy in 2005, with first approval in the US. It is a glucagon-like peptide-1 (GLP-1) receptor agonist that can be used for treatment by twice-daily injection. A long-acting release formulation for once-weekly injection is in clinical development. Clinical studies and postmarketing experience with exenatide have shown a significant and sustained reduction in glycosylated haemoglobin (HbA1c) by approximately 1 together with other gylcaemic parameters without an intrinsic risk for hypoglycaemias, and a reduction in bodyweight by 5.3kg in 82 weeks. Blood pressure and lipids are also favourably affected, but hard cardiovascular endpoints are not yet available. Animal studies show an improvement of β-cell function and an increase in β-cell mass after exenatide treatment. The most frequent adverse events associated with exenatide therapy are nausea and antibody formation (both approximately 40). Nausea, mostly mild and transient, was responsible for a 6 dropout rate in clinical studies. A recent review on the association of acute pancreatitis with exenatide treatment showed no increased risk (relative risk 1.0; 95 CI 0.6, 1.7). This review gives a benefit-risk assessment of exenatide. © 2010 Adis Data Information BV. All rights reserved.

Objective: The objective of this study was to check the reproducibility and influencing parameters of landmarks on three-dimensional images of 4- to 6-year-old Caucasian children. Probands and Methods: We examined the reproducibility of 22 landmarks on six three-dimensional facial scans of 4- to 6-yearold randomly-selected kindergarten children. The 3D scans were taken by the digital system faceSCAN II® under standardized conditions. One specially-trained investigator marked all landmarks on each of the six 3D scans a total of ten times. Ten different orthodontic residents also placed all landmarks on each of these scans. Standard deviations from the mean were then calculated from the data for each individual landmark on the x-, y- and z-axes. Results: The specially-trained investigator who had placed all landmarks on each of the six 3D scans a total of ten times found 15 of 22 landmarks to be reproducible well to within a standard deviation of less than 1 mm on each spatial plane. For the ten orthodontic residents, only three landmarks were found to be reproducible to within a standard deviation of under 1 mm for each spatial plane. Conclusion: Familiarity with 3D facial scans and their corresponding software programs, together with good image quality, improve the reproducibility of the analysis. Landmarks revealing poor reproducibility should be used, if at all, with due caution for analysis. It remains to be seen whether they can be omitted altogether, or whether they should be re-set. © 2010 Urban & Vogel, Muenchen.

Schmidt B.,Childrens Hospital of Philadelphia | Schmidt B.,McMaster University | Whyte R.K.,Dalhousie University | Asztalos E.V.,University of Toronto | And 5 more authors.
JAMA - Journal of the American Medical Association | Year: 2013

Importance: The goal of oxygen therapy is to deliver sufficient oxygen to the tissues while minimizing oxygen toxicity and oxidative stress. It remains uncertain what values of arterial oxygen saturations achieve this balance in preterm infants. Objective: To compare the effects of targeting lower or higher arterial oxygen saturations on the rate of death or disability in extremely preterm infants. Design, Setting, and Participants: Randomized, double-blind trial in 25 hospitals in Canada, the United States, Argentina, Finland, Germany, and Israel in which 1201 infants with gestational ages of 23 weeks 0 days through 27 weeks 6 days were enrolled within 24 hours after birth between December 2006 and August 2010. Follow-up assessments began in October 2008 and ended in August 2012. Interventions: Study participants were monitored until postmenstrual ages of 36 to 40 weeks with pulse oximeters that displayed saturations of either 3% above or below the true values. Caregivers adjusted the concentration of oxygen to achieve saturations between 88% and 92%, which produced 2 treatment groups with true target saturations of 85% to 89% (n=602) or 91% to 95% (n=599). Alarms were triggered when displayed saturations decreased to 86% or increased to 94%. Main Outcomes and Measures: The primary outcome was a composite of death, gross motor disability, cognitive or language delay, severe hearing loss, or bilateral blindness at a corrected age of 18 months. Secondary outcomes included retinopathy of prematurity and brain injury. Results: Of the 578 infants with adequate data for the primary outcome who were assigned to the lower target range, 298 (51.6%) died or survived with disability compared with 283 of the 569 infants (49.7%) assigned to the higher target range (odds ratio adjusted for center, 1.08; 95% CI, 0.85 to 1.37; P=.52). The rates of death were 16.6% for those in the 85% to 89% group and 15.3% for those in the 91% to 95% group (adjusted odds ratio, 1.11; 95% CI, 0.80 to 1.54; P=.54). Targeting lower saturations reduced the postmenstrual age at last use of oxygen therapy (adjusted mean difference, -0.8 weeks; 95% CI, -1.5 to -0.1; P=.03) but did not alter any other outcomes. Conclusion and Relevance In extremely preterm infants, targeting oxygen saturations of 85% to 89% compared with 91% to 95% had no significant effect on the rate of death or disability at 18 months. These results may help determine the optimal ©2013 American Medical Association. All rights reserved.

Robinson D.G.,University of Heidelberg | Pimpl P.,University of Tubingen
Trends in Plant Science | Year: 2014

Clathrin-coated vesicles (CCVs) are formed at the plasma membrane and act as vectors for endocytosis. They also assemble at the trans-Golgi network (TGN), but their exact function at this organelle is unclear. Recent studies have examined the effects on vacuolar and secretory protein transport of knockout mutations of the adaptor protein 1 (AP1) μ-adaptin subunit AP1. M, but these investigations do not clarify the situation. These mutations lead to the abrogation of multiple trafficking pathways at the TGN and cannot be used as evidence in favour of CCVs being agents for receptor-mediated export of vacuolar proteins out of the TGN. This transport process could just as easily occur through the maturation of the TGN into intermediate compartments that subsequently fuse with the vacuole. © 2013 Elsevier Ltd.

Nowak M.,University of Tubingen
American Mineralogist | Year: 2015

Gaseous sulfur compounds are critical climate active volatile components released by volcanoes. Volcanic eruptions can emit massive amounts of H2S and SO2 into the atmosphere, which react with oxygen and H2O to sulfuric acid. Formation of H2SO4 aerosols, which have on a geological timescale short-term residence times of month or years, may have global climatic impact. The phase stability of sulfur-bearing minerals such as anhydrite in erupting magmas may be a key controlling factor limiting SO2 emission during subaerial volcanic activity (Huang and Keppler, January 2015 issue of American Mineralogist). © 2015 by Walter de Gruyter Berlin/Boston 2015.

Mackenzie I.R.A.,University of British Columbia | Frick P.,German Center for Neurodegenerative Diseases | Neumann M.,German Center for Neurodegenerative Diseases | Neumann M.,University of Tubingen
Acta Neuropathologica | Year: 2014

An abnormal expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) is the most common genetic abnormality in familial and sporadic FTLD and ALS and the cause in most families where both, FTLD and ALS, are inherited. Pathologically, C9ORF72 expansion cases show a combination of FTLD-TDP and classical ALS with abnormal accumulation of TDP-43 into neuronal and oligodendroglial inclusions consistently seen in the frontal and temporal cortex, hippocampus and pyramidal motor system. In addition, a highly specific feature in C9ORF72 expansion cases is the presence of ubiquitin and p62 positive, but TDP-43 negative neuronal cytoplasmic and intranuclear inclusions. These TDP-43 negative inclusions contain dipeptide-repeat (DPR) proteins generated by unconventional repeat-associated translation of C9ORF72 transcripts with the expanded repeats and are most abundant in the cerebellum, hippocampus and all neocortex regions. Another consistent pathological feature associated with the production of C9ORF72 transcripts with expanded repeats is the formation of nuclear RNA foci that are frequently observed in the frontal cortex, hippocampus and cerebellum. Here, we summarize the complexity and heterogeneity of the neuropathology associated with the C9ORF72 expansion. We discuss implications of the data to the current classification of FTLD and critically review current insights from clinico-pathological correlative studies regarding the fundamental questions as to what processes are required and sufficient to trigger neurodegeneration in C9ORF72 disease pathogenesis. © 2013 Springer-Verlag Berlin Heidelberg.

Martens U.,University of Tubingen
German medical science : GMS e-journal | Year: 2010

Treatment of functional bowel disorders of irritable bowel-type (IBS) in children remains a difficult task because of a lack of drugs with low adverse event profile. We here report the results of a treatment study in 203 children (66 boys and 137 girls) age 4 to 18 years (mean: 10.5+/-4.5 years) with typical IBS symptoms with abdominal pain and either predominant diarrhea (n=50), constipation (n=56), alternating stool frequency (n=28) or unspecific pain (n=69). The average duration of symptoms prior to therapy was 175 days. Most (95%) patients up to age 11 were treated with a daily dose of 10 drops of Symbioflor 2 (SF2) (SymbioPharm, Herborn) (cells and autolysate of 1.5-4.5x10(7) CFU of bacteria of Escherichia coli type), in the elder children 77% received this dosage, while the remaining received a higher dose up to 30 drops/day. Treatment lasted 43 days on average. RESULTS: All patients tolerated the treatment well and without adverse events. The key IBS symptoms (abdominal pain, stool frequency) as well as the other symptoms (bloating, mucous and blood in stool, need for straining at stools, urge to defecate) improved significantly during treatment. Global assessment of therapy by parents and doctors was altogether positive. In summary these data confirm efficacy and tolerability of this probiotic compound in children and adolescents and supplement published data of probiotic IBS therapy in adults.

MYC oncoproteins are involved in the genesis and maintenance of the majority of human tumors but are considered undruggable. By using a direct in vivo shRNA screen, we show that liver cancer cells that have mutations in the gene encoding the tumor suppressor protein p53 (Trp53 in mice and TP53 in humans) and that are driven by the oncoprotein NRAS become addicted to MYC stabilization via a mechanism mediated by aurora kinase A (AURKA). This MYC stabilization enables the tumor cells to overcome a latent G2/M cell cycle arrest that is mediated by AURKA and the tumor suppressor protein p19ARF. MYC directly binds to AURKA, and inhibition of this protein–protein interaction by conformation-changing AURKA inhibitors results in subsequent MYC degradation and cell death. These conformation-changing AURKA inhibitors, with one of them currently being tested in early clinical trials, suppressed tumor growth and prolonged survival in mice bearing Trp53-deficient, NRAS-driven MYC-expressing hepatocellular carcinomas (HCCs). TP53-mutated human HCCs revealed increased AURKA expression and a positive correlation between AURKA and MYC expression. In xenograft models, mice bearing TP53-mutated or TP53-deleted human HCCs were hypersensitive to treatment with conformation-changing AURKA inhibitors, thus suggesting a therapeutic strategy for this subgroup of human HCCs. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Cantin A.M.,Universite de Sherbrooke | Hartl D.,University of Tubingen | Konstan M.W.,Case Western Reserve University | Chmiel J.F.,Case Western Reserve University
Journal of Cystic Fibrosis | Year: 2015

Lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Although CF lung disease is primarily an infectious disorder, the associated inflammation is both intense and ineffective at clearing pathogens. Persistent high-intensity inflammation leads to permanent structural damage of the CF airways and impaired lung function that eventually results in respiratory failure and death. Several defective inflammatory responses have been linked to cystic fibrosis transmembrane conductance regulator (CFTR) deficiency including innate and acquired immunity dysregulation, cell membrane lipid abnormalities, various transcription factor signaling defects, as well as altered kinase and toll-like receptor responses. The inflammation of the CF lung is dominated by neutrophils that release oxidants and proteases, particularly elastase. Neutrophil elastase in the CF airway secretions precedes the appearance of bronchiectasis, and correlates with lung function deterioration and respiratory exacerbations. Anti-inflammatory therapies are therefore of particular interest for CF lung disease but must be carefully studied to avoid suppressing critical elements of the inflammatory response and thus worsening infection. This review examines the role of inflammation in the pathogenesis of CF lung disease, summarizes the results of past clinical trials and explores promising new anti-inflammatory options. © 2015 European Cystic Fibrosis Society.

Buchfink B.,University of Tubingen
Nature Methods | Year: 2014

The alignment of sequencing reads against a protein reference database is a major computational bottleneck in metagenomics and data-intensive evolutionary projects. Although recent tools offer improved performance over the gold standard BLASTX, they exhibit only a modest speedup or low sensitivity. We introduce DIAMOND, an open-source algorithm based on double indexing that is 20,000 times faster than BLASTX on short reads and has a similar degree of sensitivity. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

The dynamics of β-amyloid deposition and related second-order physiological effects, such as regional cerebral blood flow (rCBF), are key factors for a deeper understanding of Alzheimer's disease (AD). We present longitudinal in vivo data on the dynamics of β-amyloid deposition and the decline of rCBF in two different amyloid precursor protein (APP) transgenic mouse models of AD. Using a multiparametric positron emission tomography and magnetic resonance imaging approach, we demonstrate that in the presence of cerebral β-amyloid angiopathy (CAA), β-amyloid deposition is accompanied by a decline of rCBF. Loss of perfusion correlates with the growth of β-amyloid plaque burden but is not related to the number of CAA-induced microhemorrhages. However, in a mouse model of parenchymal β-amyloidosis and negligible CAA, rCBF is unchanged. Because synaptically driven spontaneous network activity is similar in both transgenic mouse strains, we conclude that the disease-related decline of rCBF is caused by CAA. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

After application of an analytical transformation, a new exact representation for the nuclear isospin-symmetry-breaking correction δC to superallowed β decay is obtained. The correction is shown to be essentially the reciprocal of the square of an energy parameter ΩM which characterizes the charge-exchange monopole strength distribution. The proportionality coefficient in this relation is determined by basic properties of the ground state of the even-even parent nucleus and should be reliably calculable in any realistic nuclear model. Therefore, the single parameter ΩM contains all the information about the properties of excited 0+ states needed to describe δC. This parameter can possibly be determined experimentally by charge-exchange reactions. Basic quantities of interest are calculated within the isospin-consistent continuum random phase approximation, and the values of δC are compared with the corresponding results from other approaches. © 2013 American Physical Society.

Lander S.K.,University of Tubingen
Physical Review Letters | Year: 2013

The interior of a neutron star is likely to be predominantly a mixture of superfluid neutrons and superconducting protons. This results in the quantization of the star's magnetic field into an array of thin flux tubes, producing a macroscopic force very different from the Lorentz force of normal matter. We show that in an axisymmetric superconducting equilibrium the behavior of a magnetic field is governed by a single differential equation. Solving this, we present the first self-consistent superconducting neutron star equilibria with poloidal and mixed poloidal-toroidal fields and also give the first quantitative results for the corresponding magnetically induced distortions to the star. The poloidal component is dominant in all our configurations. We suggest that the transition from normal to superconducting matter in a young neutron star may cause a large-scale field rearrangement. © 2013 American Physical Society.

Human UDP-glucuronosyltransferases (UGTs) are major phase II enzymes in the drug metabolism system. Despite major advances in characterization of UGT gene family members, their role in clearance and homeostasis of endogenous substrates is insufficiently understood. Endobiotic substrates including bilirubin, serotonin, eicosanoids, steroid hormones, bile acids, thyroxine and fat-soluble vitamins A and D are discussed. Species- and tissue/cell-dependent regulation of UGT expression by ligand-activated transcription factors is often involved in endobiotic homeostasis. However, roles of particular UGTs are often difficult to delineate since they function together with other enzymes and transporters. Better knowledge of endobiotic UGT substrates and consequences of their conjugation may help to understand evolutionary conserved UGT functions. © 2015 Elsevier Inc.All rights reserved.

Dubljevic V.,University of Tubingen | Dubljevic V.,University of Stuttgart
Neuroethics | Year: 2013

This paper examines the claims in the debate on cognitive enhancement in neuroethics that society wide pressure to enhance can be expected in the near future. The author uses rational choice modeling to test these claims and proceeds with the analysis of proposed types of solutions. The discourage use, laissez-faire and prohibition types of policy are scrutinized for effectiveness, legitimacy and associated costs. Special attention is given to the moderately liberal discourage use policy (and the gate-keeper and taxation approaches within this framework), as many authors presuppose that this type of policy would best serve public interest. Different more or less articulated models in the taxation approach (Tobacco regulation analogy, Coffee-shop system, Regulatory Authority for Cognitive Enhancements and Economic Disincentives Model) are analyzed from the point of view of justificatory liberalism. The author concludes that prohibition and laissez-faire types of policy would neither be effective nor justified. A moderately liberal public policy shows more promise, but not all approaches within this type of policy would be legitimate and effective. The "gate-keeper" approach and related models could not be justified whereas approach based on taxation with suitable models might be legitimate and effective. © 2012 Springer Science+Business Media Dordrecht.

Weinstock C.,Red Cross | Schnaidt M.,University of Tubingen
International Journal of Immunogenetics | Year: 2013

The Luminex xMAP system has become an important tool for HLA antibody screening and identification in sera of transplant patients. Recently, the Luminex single antigen bead assay was shown to be prone to an artefact, the so called prozone phenomenon: Sera with high titer HLA antibodies gave negative results when tested neat, but reacted strongly positive after 1:10 dilution. We also observed such a phenomenon and found that it was most likely caused by the complement component 1 (C1) by competitively displacing the detection antibodies. In this article we review the complement-mediated prozone effect and other mechanisms of interference with solid phase assays, and we discuss possible consequences for HLA antibody testing with the Luminex SAB assay. © 2012 Blackwell Publishing Ltd.

Rossler O.E.,University of Tubingen
International Journal of Bifurcation and Chaos | Year: 2012

The pre-history of chaos in a rationalist context is taken as a point of departure, starting out with ancient China. The related ancient-Greek "unmixing theory" then leads over to two simple formally 2-body Hamiltonian systems exhibiting chaotic behavior. When the two masses involved are unequal, "pseudoattractors" are formed. Deterministic statistical "thermodynamics" with its dissipative behavior arises when the potential is repulsive. Deterministic statistical "cryodynamics" arises when the potential is attractive. The latter class of Newtonian systems is characterized by "antidissipative" behavior. A geometric proof is sketched in the footsteps of Sinai and Bunimovich. Antidissipative behavior is known empirically from Hubble's law which was so far explained in less fundamental terms. Three experimental examples are proposed. © 2012 World Scientific Publishing Company.

Lander S.K.,University of Southampton | Lander S.K.,University of Tubingen | Jones D.I.,University of Southampton
Monthly Notices of the Royal Astronomical Society | Year: 2012

We construct barotropic stellar equilibria, containing magnetic fields with both poloidal and toroidal field components. We extend earlier results by exploring the effect of different magnetic field and current distributions. Our results suggest that the boundary treatment plays a major role in determining whether the poloidal or toroidal field component is globally dominant. Using time evolutions we provide the first stability test for mixed poloidal-toroidal fields in barotropic stars, finding that all these fields suffer instabilities due to one of the field components: these are localized around the pole for toroidal-dominated equilibria and in the closed-field line region for poloidal-dominated equilibria. Rotation provides only partial stabilization. There appears to be very limited scope for the existence of stable magnetic fields in barotropic stars. We discuss what additional physics from real stars may allow for stable fields. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.

Dudai Y.,Weizmann Institute of Science | Dudai Y.,New York University | Karni A.,Haifa University | Born J.,University of Tubingen
Neuron | Year: 2015

Memory consolidation refers to the transformation over time of experience-dependent internal representations and their neurobiological underpinnings. The process is assumed to be embodied in synaptic and cellular modifications at brain circuits in which the memory is initially encoded and to proceed by recurrent reactivations, both during wakefulness and during sleep, culminating in the distribution of information to additional locales and integration of new information into existing knowledge. We present snapshots of our current knowledge and gaps in knowledge concerning the progress of consolidation over time and the cognitive architecture that supports it and shapes our long-term memories. © 2015 Elsevier Inc.

Karnath H.-O.,University of Tubingen | Karnath H.-O.,University of South Carolina
Neuropsychologia | Year: 2015

It has been established that processes relating to 'spatial attention' are implemented at cortical level by goal-directed (top-down) and stimulus-driven (bottom-up) networks. Spatial neglect in brain-damaged individuals has been interpreted as a distinguished exemplar for a disturbance of these processes. The present paper elaborates this assumption. Functioning of the two attentional networks seem to dissociate in spatial neglect; behavioral studies of patients' orienting and exploration behavior point to a disturbed stimulus-driven but preserved goal-directed attention system. When a target suddenly appears somewhere in space, neglect patients demonstrate disturbed detection and orienting if it is located in contralesional direction. In contrast, if neglect patients explore a scene with voluntarily, top-down controlled shifts of spatial attention, they perform movements that are oriented into all spatial directions without any direction-specific disturbances. The paper thus argues that not the top-down control of spatial attention itself, rather a body-related matrix on top of which this process is executed, seems affected. In that sense, the traditional role of spatial neglect as a stroke model for 'spatial attention' requires adjustment. Beyond its insights into the human stimulus-driven attentional system, the disorder most notably provides vistas in how our brain encodes topographical information and organizes spatially oriented action - including the top-down control of spatial attention - in relation to body position. © 2015 Elsevier Ltd.

Pietsch D.,University of Tubingen
Catena | Year: 2013

Krotovinas, the burrows of small mammals, are common phenomena in steppe landscapes, and for a long time they have been a major point of discussions about the genesis of Holocene Chernozems. In addition, krotovinas provide a very valuable archive of the biological activities of soil, which is essential when stratigraphical ambiguities are to be solved. Despite this, krotovinas have received little attention within pedostratigraphical research. Using the example of the Upper Palaeolithic excavations Kostiënki and Borshchevo in the Middle Russian Steppe an integrative soil scientific approach highlights the importance of burrowing small mammals and of krotovina fillings resulting from both bioturbation and soil erosion in the Late Pleistocene. Based on field and laboratory data of sediments inside and outside krotovinas and 14C dating results from two sections, this systematic approach demonstrates the high value of the burrow fillings: black and humus-speckled fillings belong to deep burrows of hamsters dating to the period of Early Holocene Chernozem formation at the very beginning of the Preboreal (10-8kacal BC). Greyish sediments originate either from Ag-Bg horizons of the "Gmelin soil" (25-22ka) or from other as yet unknown Late Valdai paleosols; these fillings are the result of the activities of shallow-burrowing lemmings. In addition, burrow fillings have provided optimal material for worms. Also, fossil bones and teeth found within krotovina fillings give new insights into the occurrence of Cricetus cricetus and Lagurus lagurus in this part of the Middle Russian steppe. © 2012 Elsevier B.V.

Rothenberger L.G.,University of Tubingen
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2012

Immense resource allocations have led to great data output in genetic research. Concerning ADHD resources spent on genetic research are less than those spent on clinical research. But there are successful efforts made to increase support for molecular genetics research in ADHD. Concerning genetics no evidence based conclusive results have significant impact on prevention, diagnosis or treatment yet. With regard to ethical aspects like the patients' benefit and limited resources the question arises if it is indicated to think about a new balance of resource allocation between molecular genetics and non-genetics research in ADHD. An ethical reflection was performed focusing on recent genetic studies and reviews based on a selective literature search. There are plausible reasons why genetic research results in ADHD are somehow disappointing for clinical practice so far. Researchers try to overcome these gaps systematically, without knowing what the potential future benefits for the patients might be. Non-genetic diagnostic/therapeutic research may lead to clinically relevant findings within a shorter period of time. On the other hand, non-genetic research in ADHD may be nurtured by genetic approaches. But, with the latter there exist significant risks of harm like stigmatization and concerns regarding data protection. Isolated speeding up resources of genetic research in ADHD seems questionable from an ethical point of view. There is a need to find a new balance of resource allocation between genetic and non-genetic research in ADHD, probably by integrating genetics more systematically into clinical research. A transdisciplinary debate is recommended. © 2012 Wiley Periodicals, Inc.

Schurig V.,University of Tubingen
Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences | Year: 2011

The historical development of the enantioseparation of derivatized α-amino acids by high-resolution capillary gas chromatography on chiral stationary phases derived from α-amino acid-derivatives and modified cyclodextrins is described. The pioneering work emerging from Emanuel Gil-Av and his associates at the Weizmann Institute of Science is reviewed. A bridge to more recent developments is spanned aimed at helping to select appropriate tools for contemporary chiral α-amino acid analysis by gas chromatography in different research areas. © 2011 Elsevier B.V.

Filik R.,University of Nottingham | Leuthold H.,University of Tubingen
Brain Research | Year: 2013

Little is known about the on-line evaluation of information relating to well-known story characters during text comprehension. For example, it is not clear in how much detail readers represent character-based information, and the time course over which this information is utilized during on-line language comprehension. We describe an event-related potential (ERP) study (Experiment 1) and an eye-tracking study (Experiment 2) investigating whether, and when, readers utilize their prior knowledge of a character in processing event information. Participants read materials in which an event was described that either did or did not fit with the character's typical behavior. ERPs elicited by the critical word revealed an N400 effect when the action described did not fit with the character's typical behavior. Results from early eye movement measures supported these findings, and later measures suggested that such violations were more easily accommodated for well-known fictional characters than real-world characters. © 2013 Elsevier B.V.

Colautti R.I.,University of Tubingen | Lau J.A.,Michigan State University
Molecular Ecology | Year: 2015

Biological invasions are 'natural' experiments that can improve our understanding of contemporary evolution. We evaluate evidence for population differentiation, natural selection and adaptive evolution of invading plants and animals at two nested spatial scales: (i) among introduced populations (ii) between native and introduced genotypes. Evolution during invasion is frequently inferred, but rarely confirmed as adaptive. In common garden studies, quantitative trait differentiation is only marginally lower (~3.5%) among introduced relative to native populations, despite genetic bottlenecks and shorter timescales (i.e. millennia vs. decades). However, differentiation between genotypes from the native vs. introduced range is less clear and confounded by nonrandom geographic sampling; simulations suggest this causes a high false-positive discovery rate (>50%) in geographically structured populations. Selection differentials (s) are stronger in introduced than in native species, although selection gradients (β) are not, consistent with introduced species experiencing weaker genetic constraints. This could facilitate rapid adaptation, but evidence is limited. For example, rapid phenotypic evolution often manifests as geographical clines, but simulations demonstrate that nonadaptive trait clines can evolve frequently during colonization (~two-thirds of simulations). Additionally, QST-FST studies may often misrepresent the strength and form of natural selection acting during invasion. Instead, classic approaches in evolutionary ecology (e.g. selection analysis, reciprocal transplant, artificial selection) are necessary to determine the frequency of adaptive evolution during invasion and its influence on establishment, spread and impact of invasive species. These studies are rare but crucial for managing biological invasions in the context of global change. © 2015 John Wiley & Sons Ltd.

Blumenstock G.,University of Tubingen
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | Year: 2011

Quality in healthcare is not directly observable and measurable. Quality indicators serve as a tool for operationalizing quality of care. Different quality measures are required depending on the purpose, context, and audience concerned. The methodological quality of the indicators themselves has to be critically assessed. Various quality requirements for indicators have been published and can be described based on the steps of the devel opmental process. Importance, scientific acceptability, usability, and feasibility are reported as basic criteria for assessment. The QUALIFY instrument offers a standardized approach for assessing quality indicators and reflects best current practice. Measuring quality through indicators is no end in itself. The effect of measurement on motivating quality improvement must be evaluated in future studies. © Springer-Verlag 2011.

Kanazawa K.,Temple University | Metz A.,Temple University | Pitonyak D.,Brookhaven National Laboratory | Schlegel M.,University of Tubingen
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2015

We analyze single-spin asymmetries (SSAs) in the leptoproduction of transversely polarized Λ hyperons within the collinear twist-3 formalism. We calculate both the distribution and fragmentation terms in two different gauges (lightcone and Feynman) and show that the results are identical. This is the first time that the fragmentation piece has been analyzed for transversely polarized hadron production within the collinear twist-3 framework. In lightcone gauge we use the same techniques that were employed in computing the analogous piece in p↑p→πX, which has become an important part to that reaction. With this in mind, we also verify the gauge invariance of the formulas for the transverse SSA in the leptoproduction of pions. © 2015 The Authors.

Industry studies with an evolutionary perspective point out that spinoffs are important for the evolution of spatial industry concentrations. More and more, these studies challenge the supposed importance of agglomeration economies, especially in manufacturing industries. This paper tests in how far these results apply to the locomotive industry prior to World War I. It builds upon a new dataset consisting of steam locomotive builders in Great Britain, in the US, and in Germany and adopts descriptive survival analyses as well as estimations of Gompertz-models. The results show that spinoffs in Great Britain and in the US survived longer than other firms and that as early as in the 19th century. Agglomeration economies are particularly noticeable in form of positive effects from related industries, but play a minor role in general. Furthermore, the results show clearly that - as consequence of an alternative institutional path - the mechanisms of industrial dynamics that are evident for Great Britain and the US were not as effective in the case of Germany. © Franz Steiner Verlag, Stuttgart.

Jucker M.,University of Tubingen | Jucker M.,German Center for Neurodegenerative Diseases | Jucker M.,Hertie Institute for Clinical Brain Research | Walker L.C.,Emory University
Annals of Neurology | Year: 2011

The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are b-amyloid (Ab) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral b-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, a-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders. © 2011 American Neurological Association.

Codogno P.,University Paris - Sud | Mehrpour M.,University Paris - Sud | Proikas-Cezanne T.,University of Tubingen
Nature Reviews Molecular Cell Biology | Year: 2012

The autophagosome is the central organelle in macroautophagy, a vacuolar lysosomal catabolic pathway that degrades cytoplasmic material to fuel starving cells and eliminates intracellular pathogens. Macroautophagy has important physiological roles during development, ageing and the immune response, and its cytoprotective function is compromised in various diseases. A set of autophagy-related (ATG) proteins is hierarchically recruited to the phagophore, the initial membrane template in the construction of the autophagosome. However, recent findings suggest that macroautophagy can also occur in the absence of some of these key autophagy proteins, through the unconventional biogenesis of canonical autophagosomes. Such alternatives to the evolutionarily conserved scheme might provide additional therapeutic opportunities.

Villagran X.S.,University of Tubingen
Journal of Anthropological Archaeology | Year: 2014

The prehistory of the southern coast of Brazil (Santa Catarina state) is materialized in the present landscape by numerous large-scale shellmounds, shellmounds with a sandy core, and fishmounds. A geoarchaeological approach was applied to understand the sequence and diversity of human actions involved in the settlement of the area as expressed in the multiple mounded structures, dated from the early Holocene to shortly before the arrival of the first colonizers. A detailed account of the composition and history of four stratified shellmounds, two shellmounds with a sandy core, and two fishmounds is given using a standard method for intra and inter site comparisons. The method combines the macroscopic evaluation of the profiles with off-site sampling, provenance of the organic matter in the sediments, and micro-scale identification of components, their alteration, and arrangement. Substantial implications result from this analysis related to the identification of recurrent behaviors in shellmound formation and growth, prehistoric alteration and destruction of habitation sites, development of a built environment, and continuity in mound building as an expression of group identity. Shellmounds and fishmounds show a complex pre-depositional history that denies the traditional view of them as secondary deposits of food remains. © 2014 Elsevier Inc.

Trauzettel-Klosinski S.,University of Tubingen
Diabetologe | Year: 2015

Depending on the location, diabetic ocular manifestations can greatly affect functions relevant for daily living. Central visual field defects, as in macular edema, lead to reading disability. In peripheral retinopathy with concentric visual fields, orientation difficulties arise. Accordingly, rehabilitation measures are applied by means of visual aids and training with the aim to compensate for the visual deficit. Visual rehabilitation can be quite successful and improves patients’ independence and quality of life. © 2015, Springer-Verlag Berlin Heidelberg.

Koprivnjak T.,National Institute of Chemistry, Slovenia | Peschel A.,University of Tubingen
Cellular and Molecular Life Sciences | Year: 2011

Host defense peptides and proteins are important components of the innate host defense against pathogenic microorganisms. They target negatively charged bacterial surfaces and disrupt microbial cytoplasmic membranes, which ultimately leads to bacterial destruction. Throughout evolution, pathogens devised several mechanisms to protect themselves from deleterious damage of host defense peptides. These strategies include (a) inactivation and cleavage of host defense peptides by production of host defense binding proteins and proteases, (b) repulsion of the peptides by alteration of pathogen's surface charge employing modifications by amino acids or amino sugars of anionic molecules (e.g., teichoic acids, lipid A and phospholipids), (c) alteration of bacterial membrane fluidity, and (d) expulsion of the peptides using multi drug pumps. Together with bacterial regulatory network(s) that regulate expression and activity of these mechanisms, they represent attractive targets for development of novel antibacterials. © Springer Basel AG 2011.

Chronic inflammation promotes atherosclerosis in cardiovascular disease and is a major prognostic factor for patients undergoing percutaneous coronary intervention (PCI). Macrophage migration inhibitory factor (MIF) is involved in the progress of atherosclerosis and plaque destabilization and plays a pivotal role in the development of acute coronary syndromes (ACS). Little is known to date about the clinical impact of MIF in patients with symptomatic coronary artery disease (CAD). In a pilot study, 286 patients with symptomatic CAD (n = 119 ACS, n = 167 stable CAD) undergoing PCI were consecutively evaluated. 25 healthy volunteers served as control. Expression of MIF was consecutively measured in patients at the time of PCI. Baseline levels of interleukin 6 (IL-6), "regulated upon activation, normal T-cell expressed, and secreted" (RANTES) and monocyte chemoattractant protein-1 (MCP-1) were measured by Bio-Plex Cytokine assay. C-reactive protein (CRP) was determined by Immunoassay. Patients with ACS showed higher plasma levels of MIF compared to patients with stable CAD and control subjects (median 2.85 ng/mL, interquartile range (IQR) 3.52 versus median 1.22 ng/mL, IQR 2.99, versus median 0.1, IQR 0.09, p<0.001). Increased MIF levels were associated with CRP and IL-6 levels and correlated with troponin I (TnI) release (spearman rank coefficient: 0.31, p<0.001). Patients with ACS due to plaque rupture showed significantly higher plasma levels of MIF than patients with flow limiting stenotic lesions (p = 0.002). To our knowledge this is the first study, demonstrating enhanced expression of MIF in ACS. It is associated with established inflammatory markers, correlates with the extent of cardiac necrosis marker release after PCI and is significantly increased in ACS patients with "culprit" lesions. Further attempts should be undertaken to characterize the role of MIF for risk assessment in the setting of ACS.

Chronic graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation occurring in 6% to 65% of the recipients. Currently, the therapeutic mainstay for chronic GvHD are corticosteroids that are frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory chronic GvHD. The therapeutic options in these people include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultraviolet radiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. To evaluate the effectiveness and safety of ECP for the management of chronic GvHD in children and adolescents after haematopoietic stem cell transplantation. We searched the Cochrane Central Register of Controlled Trials (Issue 9, 2012), MEDLINE and EMBASE databases from their inception to 12 September 2012. We searched the reference lists of potentially relevant studies without any language restriction. We searched eight trial registers and five conference proceedings. We also contacted experts in the field. Randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in paediatric patients with chronic GvHD after haematopoietic stem cell transplantation. Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author. We found no studies meeting the criteria for inclusion in this review. The efficacy of ECP in the treatment of chronic GvHD in paediatric patients after haematopoietic stem cell transplantation based on RCTs can currently not be evaluated since we have found no such studies. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this patient population will be challenging due to the limited number of patients, the variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical grounds in favour of ECP are made, people should be carefully monitored for beneficial and harmful effects and efforts should be made to share this information with other clinicians, for example by setting up registries for paediatric patients that are treated with ECP.

Linder J.U.,University of Tubingen
Methods in enzymology | Year: 2010

HAMP domains are the central signal converters in bacterial chemotaxis receptors and chemosensory histidine kinases. They link the signal input modules in these proteins, that is, the ligand-binding domains, to the output modules, for example, the histidine kinase domain. A similar architecture is present in the adenylyl cyclase (AC) Rv3645 from Mycobacterium tuberculosis, where a HAMP domain is positioned between the N-terminal membrane anchor and the C-terminal catalytic domain. Because the activity of the catalytic domain responds to alterations in the HAMP domain, a method has been developed which uses the catalytic domain of Rv3645 as a reporter to probe the HAMP domain function of diverse bacterial proteins. A strategy for construction of chimeras between a variety of HAMP domains and the catalytic domain of the AC Rv3645 is described. The enzymes are overexpressed in Escherichia coli and purified by Ni2+-affinity chromatography. AC activity of the chimeras is determined by a radiotracer method published earlier in the series. Results of the mutagenesis of the HAMP domain from the Af1503 protein of Archeoglobus fulgidus are shown as an example for the successful application of the method. Copyright © 2010 Elsevier Inc. All rights reserved.

Dall'Osso S.,University of Tubingen | Giacomazzo B.,University of Trento | Giacomazzo B.,National Institute of Nuclear Physics, Italy | Perna R.,State University of New York at Stony Brook | Stella L.,National institute for astrophysics
Astrophysical Journal | Year: 2015

Binary neutron star (NS) mergers are among the most promising sources of gravitational waves (GWs), as well as candidate progenitors for short gamma-ray bursts (SGRBs). Depending on the total initial mass of the system and the NS equation of state (EOS), the post-merger phase can be characterized by a prompt collapse to a black hole or by the formation of a supramassive NS, or even a stable NS. In the latter cases of post-merger NS (PMNS) formation, magnetic field amplification during the merger will produce a magnetar and induce a mass quadrupole moment in the newly formed NS. If the timescale for orthogonalization of the magnetic symmetry axis with the spin axis is smaller than the spindown time, the NS will radiate its spin down energy primarily via GWs. Here we study this scenario for the various outcomes of NS formation: we generalize the set of equilibrium states for a twisted torus magnetic configuration to include solutions that, for the same external dipolar field, carry a larger magnetic energy reservoir; we hence compute the magnetic ellipticity for such configurations, and the corresponding strength of the expected GW signal as a function of the relative magnitude of the dipolar and toroidal field components. The relative number of GW detections from PMNSs and from binary NSs is a very strong function of the NS EOS, being higher (∼1%) for the stiffest EOSs and negligibly small for the softest ones. For intermediate-stiffness EOSs, such as the n = 4/7 polytrope recently used by Giacomazzo and Perna or the GM1 used by Lasky et al., the relative fraction is ∼0.3%; correspondingly, we estimate a GW detection rate from stable PMNSs of ∼0.1-1 yr-1 with advanced detectors, and of ∼100-1000 yr-1 with detectors of third generation such as the Einstein Telescope. Measurement of such GW signals would provide constraints on the NS EOS and, in connection with an SGRB, on the nature of the binary progenitors giving rise to these events. © 2015. The American Astronomical Society. All rights reserved.

Kanazawa K.,Temple University | Metz A.,Temple University | Pitonyak D.,Brookhaven National Laboratory | Schlegel M.,University of Tubingen
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2015

We analyze the longitudinal-transverse double-spin asymmetry in lepton-nucleon collisions where a single hadron is detected in the final state, i.e., ℓ→N↑→hX. This is a subleading-twist observable in collinear factorization, and we look at twist-3 effects in both the transversely polarized nucleon and the unpolarized outgoing hadron. Results are anticipated for this asymmetry from both HERMES and Jefferson Lab Hall A, and it could be measured as well at COMPASS and a future Electron-Ion Collider. We also perform a numerical study of the distribution term, which, when compared to upcoming experimental results, could allow one to learn about the "worm-gear"-type function g~(x) as well as assess the role of quark-gluon-quark correlations in the initial-state nucleon and twist-3 effects in the fragmenting unpolarized hadron. © 2015 The Authors.

Posth N.R.,University of Southern Denmark | Canfield D.E.,University of Southern Denmark | Kappler A.,University of Tubingen
Earth-Science Reviews | Year: 2014

Fe-metabolizing bacteria are intimately linked to the cycling of Fe in modern environments and have likely been key players in the evolution of the Earth's biogeosphere. Fe minerals have also been suggested as a key preservative of cell organic matter in sediments, keeping otherwise labile phases conserved at least on time scales of 100,000. years. The interpretation of a biological influence on the Fe rock record is difficult without a deeper understanding of the mechanisms of biogenic Fe(III) and Fe(II) mineral formation, the character of these minerals, and their diagenesis over short and long time scales. Here, we present the recent advances in the study of abiogenic and biogenic Fe(III) minerals. In particular, we focus on the role of Fe(II)-oxidizing bacteria in the deposition of ancient banded iron formations (BIF). We discuss this work within the framework of the main challenge: separating biogenic from abiogenic processes over deep time. We describe how efforts in isotope geochemistry, biomarker research, mineral analysis and biogeochemistry are helping to establish a window to the past. Finally, we present some new approaches that help investigate the main processes leading to the formation and potential fate of Fe-organic matter aggregates. © 2014 Elsevier B.V.

Himmel D.,Albert Ludwigs University of Freiburg | Krossing I.,Albert Ludwigs University of Freiburg | Schnepf A.,University of Tubingen
Angewandte Chemie - International Edition | Year: 2014

Risky business? The use of dative bonds to describe the electronic structure of main-group compounds has come into vogue in recent years. But where are the limits? When does the description as a dative bond make sense and when is this view misleading? This Essay develops the idea on the basis of current examples. © 2014 WILEY-VCH Verlag GmbH.

Kohlhepp G.,University of Tubingen
Estudos Avancados | Year: 2010

One of the aims of energy policies is reducing Co2 emissions. In transports bio-fuels are one of the alternatives. Brazil is the world leader in producing ethanol from sugar cane. Prejudice against imports of Brazilian ethanol in US and EU markets is unjustifed, as it represents the best ecological balance and does not reduce production of basic food in Brazil. As to biodiesel on the basis of soybeans social and ecological reserves partly are in order. Regarding ethanol industrialized countries should not use exaggerated criteria as to sustainability of production as pretext for protecting their own producers from imports of cheaper Brazilian bio-fuels.

Konoplya R.A.,Kyoto University | Konoplya R.A.,University of Tubingen | Zhidenko A.,University of Sao Paulo
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2010

Using the recently found by G. Horowitz and M. Roberts (arXiv:0908.3677) numerical model of the ground state of holographic superconductors (at zero temperature), we calculate the conductivity for such models. The universal relation connecting conductivity with the reflection coefficient was used for finding the conductivity by the WKB approach. The dependence of the conductivity on the frequency and charge density is discussed. Numerical calculations confirm the general arguments of (arXiv:0908.3677) in favor of non-zero conductivity even at zero temperature. In addition to the Horowitz-Roberts solution we have found (probably infinite) set of extra solutions which are normalizable and reach the same correct RN-AdS asymptotic at spatial infinity. These extra solutions (which correspond to larger values of the grand canonical potential) lead to effective potentials that also vanish at the horizon and thus correspond to a non-zero conductivity at zero temperature. © 2010 Elsevier B.V. All rights reserved.

Haug E.,University of Tubingen
European Physical Journal D | Year: 2010

Using the partial-wave formalism the cross section of bremsstrahlung for a pure Coulomb field is calculated for various atomic numbers of the target nucleus and various incident electron energies. The results are compared to those of previous theories. For intermediate and large atomic numbers the latter cross sections undervalue significantly the present ones. Except for low atomic numbers the cross sections in Born approximation with the Coulomb correction by Elwert yield more accurate results than the cross sections obtained by using the approximate Sommerfeld-Maue wave function. The effect of screening is small for low atomic numbers. At nonrelativistic energies the number of required partial waves is rather large for target nuclei with high atomic numbers, contrary to the expectations. The pertinent results exceed the numerical values including screening by factors of up to five. They verify the assumption that the nonrelativistic cross section of Sommerfeld is fairly accurate even for high atomic numbers.

Weigel H.,Stellenbosch University | Quandt M.,University of Tubingen
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2010

We improve on a method to compute the fermion contribution to the vacuum polarization energy of string-like configurations in a non-Abelian gauge theory. We establish the new method by numerically verifying the invariance under (a subset of) local gauge transformations. This also provides further support for the use of spectral methods to compute vacuum polarization energies in general. We confirm that the vacuum energy in the over(MS, -) renormalization scheme is tiny as compared to the mass of the fluctuating fermion field. Numerical results for the physical on-shell scheme are also presented. © 2010 Elsevier B.V. All rights reserved.

Pfister H.,University of Tubingen
Classical and Quantum Gravity | Year: 2010

If rotating dust stars would exist in general relativity, they would represent examples of an improbable complete balance between the attractive quasi-Newtonian force (gravitoelectricity) and the repulsive gravitomagnetism. However, nonexistence proof is available hitherto only for some dust 'stars' extending to infinity and for isolated dust stars of a very restricted class. By analyzing the lines of constant generalized Newtonian potential U in the interior and exterior of a large class of (hypothetical) stationary and axisymmetrically rotating dust stars in general relativity, we find that the existence of such stars can be disproved as soon as minima of the potential U in the exterior vacuum region can be excluded. We present some ideas of how this minimum problem could be attacked, and we summarize the present knowledge about Newtonian and Einsteinian rotating dust systems. © 2010 IOP Publishing Ltd.

Kramer P.,University of Tubingen
Classical and Quantum Gravity | Year: 2010

The cosmic microwave background (CMB) originates from an early stage in the history of the universe. Observations show low-multipole contributions of CMB fluctuations. A possible explanation is given by a non-trivial topology of the universe and has motivated the search for topological selection rules. Harmonic analysis on a topological manifold must provide basis sets for all functions compatible with a given topology and so is needed to model the CMB fluctuations. We analyze the fundamental groups of Platonic tetrahedral, cubic and octahedral manifolds using deck transformations. From them we construct the appropriate harmonic analysis and boundary conditions. We provide the algebraic means for modeling the multipole expansion of incoming CMB radiation. From the assumption of randomness, we derive selection rules, depending on the point symmetry of the manifold. © 2010 IOP Publishing Ltd.

Heni M.,University of Tubingen
The Journal of clinical endocrinology and metabolism | Year: 2013

Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models. To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content. We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%). Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by (1)H-magnetic resonance spectroscopy were performed. SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin-related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected. We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism.

Elsenbruch S.,University of Duisburg - Essen | Enck P.,University of Tubingen
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Placebo effects in clinical trials have sparked an interest in the placebo phenomenon, both in randomized controlled trials (RCTs) and in experimental gastroenterology. RCTs have demonstrated similar short-term and long-term placebo response rates in gastrointestinal compared to other medical diagnoses. Most mediators and moderators of placebo effects in gastrointestinal diseases are also of similar type and size to other medical diagnoses and not specific for gastrointestinal diagnoses. Other characteristics such as an increase in the placebo response over time and the placebo-enhancing effects of unbalanced randomization were not seen, at least in IBS. Experimental placebo and nocebo studies underscore the 'power' of expectancies and conditioning processes in shaping gastrointestinal symptoms not only at the level of self-reports, but also within the brain and along the brain-gut axis. Brain imaging studies have redressed earlier criticism that placebo effects might merely reflect a response bias. These findings raise hope that sophisticated trials and experiments designed to boost positive expectations and minimize negative expectations could pave the way for a practical and ethically sound use of placebo knowledge in daily practice. Rather than focusing on a 'personalized' choice of drugs based on biomarkers or genes, it might be the doctor-patient communication that needs to be tailored. © 2015 Macmillan Publishers Limited.

Bettinger H.F.,University of Tubingen
Pure and Applied Chemistry | Year: 2010

The hypothetical polymer obtained by linear annelation of benzene units, polyacene (PAC) (C4H2)n, has received considerable attention over the last 50 years. This interest is due to the unusual electronic structure that is assumed to result in usual physical properties. The review summarizes the theoretical investigations of PAC research. The most recent computational analyses available in the literature are based on density functional theory (DFT) for PAC and on the complete active space self-consistent field (CASSCF) method for oligoacenes and suggest an undistorted symmetrical structure with an antiferromagnetic (AFM) coupling of electrons. © 2010 IUPAC.

Funke K.,Ruhr University Bochum | Benali A.,University of Tubingen
Journal of Physiology | Year: 2011

Transcranial magnetic stimulation (TMS) has become a popular method to non-invasively stimulate the human brain. The opportunity to modify cortical excitability with repetitive stimulation (rTMS) has especially gained interest for its therapeutic potential. However, details of the cellular mechanisms of the effects of rTMS are scarce. Currently favoured are long-term changes in the efficiency of excitatory synaptic transmission, with low-frequency rTMS depressing it, but high-frequency rTMS augmenting. Only recently has modulation of cortical inhibition been considered as an alternative way to explain lasting changes in cortical excitability induced by rTMS. Adequate animal models help to highlight stimulation-induced changes in cellular processes which are not assessable in human rTMS studies. In this review article, we summarize findings obtained with our rat models which indicate that distinct inhibitory cell classes, like the fast-spiking cells characterized by parvalbumin expression, are most sensitive to certain stimulation protocols, e.g. intermittent theta burst stimulation. We discuss how our findings can support the recently suggested models of gating and homeostatic plasticity as possible mechanisms of rTMS-induced changes in cortical excitability. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.

Tremmel J.C.,University of Tubingen
Environmental Values | Year: 2013

Climate change poses a serious problem for established ethical theories. There is no dearth of literature on the subject of climate ethics that break down the complexity of the issue, thereby enabling one to arrive at partial conclusions such as: 'historical justice demands us to do this...' or 'intergenerational justice demands us to do that...'. In contrast, this article attempts to face up to this complexity, that is: to end with a synthesis of the arguments into what can be considered to be the most reasonable and fairest approach to the politics of climate change on a global scale. A significant part of the paper is devoted to the questions whether or not a) historical emissions and b) population changes are relevant to how emissions rights should be distributed. I discuss the merits and drawbacks of each perspective and briefly outline the normative justifications. © 2013 The White Horse Press.

Bantel H.,Hannover Medical School | Schulze-Osthoff K.,University of Tubingen
Frontiers in Physiology | Year: 2012

Acute liver failure (ALF) can be the consequence of various etiologies, that might vary between different geographic regions. Most frequent are intoxications with acetaminophen, viral hepatitis, or liver damage of unknown origin. ALF occurs when the extent of hepatocyte death exceeds the regenerative capacity of the liver. The mode of liver cell death that is predominantly induced in ALF, i.e., apoptosis or necrosis, is still controversial and presumably determined by the etiology, duration, and magnitude of liver injury. Severe liver damage involves oxidative stress and depletion of ATP resulting in necrosis. In contrast, maintenance of ATP stores is required for the execution of apoptosis. Recent data suggest that necrosis resulting from severe liver damage is associated with poor outcome of ALF patients. Discrimination between apoptosis and necrosis might be therefore useful for the identification of ALF patients requiring liver transplantation. Identification of the molecular cell death mechanisms remains an important issue not only for early prediction of ALF outcome, but also for therapeutic interventions. In view of the pleiotropic functions of critical mediators of cell death and tissue regeneration, a particular challenge will be to reduce hepatocellular death without inhibiting the regenerative capacity of the liver. Here, we review the molecular mechanisms of hepatocyte injury and the pathways leading to apoptosis and necrosis, which might represent potential diagnostic and therapeutic targets in ALF.

Herschel M.,University of Tubingen | Hernandez M.A.,IBM
Proceedings of the VLDB Endowment | Year: 2010

This paper addresses the problem of explaining missing answers in queries that include selection, projection, join, union, aggregation and grouping (SPJUA). Explaining missing answers of queries is useful in various scenarios, including query understanding and debugging. We present a general framework for the generation of these explanations based on source data. We describe the algorithms used to generate a correct, finite, and, when possible, minimal set of explanations. These algorithms are part of Artemis, a system that assists query developers in analyzing queries by, for instance, allowing them to ask why certain tuples are not in the query results. Experimental results demonstrate that Artemis generates explanations of missing tuples at a pace that allows developers to effectively use them for query analysis. © 2010 VLDB Endowment.

Zeth K.,University of Tubingen
Biochemical Journal | Year: 2012

Dps proteins are the structural relatives of bacterioferritins and ferritins ubiquitously present in the bacterial and archaeal kingdoms. The ball-shaped enzymes play important roles in the detoxification of ROS (reactive oxygen species), in iron scavenging to prevent Fenton reactions and in the mechanical protection of DNA. Detoxification of ROS and iron chaperoning represent the most archetypical functions of dodecameric Dps enzymes. Recent crystallographic studies of these dodecameric complexes have unravelled species-dependent mechanisms of iron uptake into the hollow spheres. Subsequent functions in iron oxidation at ferroxidase centres are highly conserved among bacteria. Final nucleation of iron as iron oxide nanoparticles has been demonstrated to originate at acidic residues located on the inner surface. Some Dps enzymes are also implicated in newly observed catalytic functions related to the formation of molecules playing roles in bacterium-host cell communication. Most recently, Dps complexes are attracting attention in semiconductor science as biomimetic tools for the technical production of the smallest metal-based quantum nanodots used in nanotechnological approaches, such as memory storage or solar cell development. © The Authors Journal compilation © 2012 Biochemical Society.

Keppeler S.,University of Tubingen | Sjodahl M.,Lund University
Journal of High Energy Physics | Year: 2012

We develop a general recipe for constructing orthogonal bases for the calculation of color structures appearing in QCD for any number of partons and arbitrary Nc. The bases are constructed using hermitian gluon projectors onto irreducible subspaces invariant under SU(Nc). Thus, each basis vector is associated with an irreducible representation of SU(Nc). The resulting multiplet bases are not only orthogonal, but also minimal for finite Nc. As a consequence, for calculations involving many colored particles, the number of basis vectors is reduced significantly compared to standard approaches employing over complete bases. We exemplify the method by constructing multiplet bases for all processes involving a total of 6 external colored partons. © SISSA 2012.

Muller S.,University of Tubingen
Protoplasma | Year: 2012

Coordinated cell divisions and cell expansion are the key processes that command growth in all organisms. The orientation of cell divisions and the direction of cell expansion are critical for normal development. Symmetric divisions contribute to proliferation and growth, while asymmetric divisions initiate pattern formation and differentiation. In plants these processes are of particular importance since their cells are encased in cellulosic walls that determine their shape and lock their position within tissues and organs. Several recent studies have analyzed the relationship between cell shape and patterns of symmetric cell division in diverse organisms and employed biophysical and mathematical considerations to develop computer simulations that have allowed accurate prediction of cell division patterns. From these studies, a picture emerges that diverse biological systems follow simple universal rules of geometry to select their division planes and that the microtubule cytoskeleton takes a major part in sensing the geometric information and translates this information into a specific division outcome. In plant cells, the division plane is selected before mitosis, and spatial information of the division plane is preserved throughout division by the presence of reference molecules at a distinct region of the plasma membrane, the cortical division zone. The recruitment of these division zone markers occurs multiple times by several mechanisms, suggesting that the cortical division zone is a highly dynamic region. © 2011 Springer-Verlag.

Konoplya R.A.,Kyoto University | Konoplya R.A.,University of Tubingen | Zhidenko A.,University of Sao Paulo | Zhidenko A.,Federal University of ABC
Reviews of Modern Physics | Year: 2011

Perturbations of black holes, initially considered in the context of possible observations of astrophysical effects, have been studied for the past 10 years in string theory, brane-world models, and quantum gravity. Through the famous gauge/gravity duality, proper oscillations of perturbed black holes, called quasinormal modes, allow for the description of the hydrodynamic regime in the dual finite temperature field theory at strong coupling, which can be used to predict the behavior of quark-gluon plasmas in the nonperturbative regime. On the other hand, the brane-world scenarios assume the existence of extra dimensions in nature, so that multidimensional black holes can be formed in a laboratory experiment. All this stimulated active research in the field of perturbations of higher-dimensional black holes and branes during recent years. In this review recent achievements on various aspects of black hole perturbations are discussed such as decoupling of variables in the perturbation equations, quasinormal modes (with special emphasis on various numerical and analytical methods of calculations), late-time tails, gravitational stability, anti-de Sitter/conformal field theory interpretation of quasinormal modes, and holographic superconductors. We also touch on state-of-the-art observational possibilities for detecting quasinormal modes of black holes. © 2011 American Physical Society.

Acioly M.A.,University of Tubingen | Acioly M.A.,University of Sao Paulo
Neurosurgery | Year: 2010

This study was conducted to investigate the success rate of using the facial motor evoked potential (FMEP) of orbicularis oculi and oris muscles for facial nerve function monitoring with use of a stepwise protocol, and its usefulness in predicting facial nerve outcome during cerebellopontine angle (CPA) surgeries. FMEPs were recorded intraoperatively from 60 patients undergoing CPA surgeries. Transcranial electrocortical stimulation (TES) was performed using corkscrew electrodes positioned at hemispheric montage (C3/C4 and CZ). The contralateral abductor pollicis brevis muscle was used as the control response. Stimulation was always applied contralaterally to the affected side using 1, 3, or 5 rectangular pulses ranging from 200 to 600 V with 50 micros of pulse duration and an interstimulus interval of 2 ms. Facial potentials were recorded from needles placed in the orbicularis oculi and oris muscles. FMEP from the orbicularis oris and oculi muscles could be reliably monitored in 86.7% and 85% of the patients, respectively. The immediate postoperative facial function correlated significantly with the FMEP ratio in the orbicularis oculi muscle at 80% amplitude ratio (P = .037) and orbicularis oris muscle at 35% ratio (P = .000). FMEP loss was always related to postoperative facial paresis, although in different degrees. FMEPs can be obtained reliably by using TES with 3 to 5 train pulses. Stable intraoperative FMEPs can predict a good postoperative outcome of facial function. However, further refinements of this technique are necessary to minimize artifacts and to make this method more reliable.

Eisenberg D.,Howard Hughes Medical Institute | Jucker M.,University of Tubingen | Jucker M.,German Center for Neurodegenerative Diseases
Cell | Year: 2012

Amyloid fibers and oligomers are associated with a great variety of human diseases including Alzheimer's disease and the prion conditions. Here we attempt to connect recent discoveries on the molecular properties of proteins in the amyloid state with observations about pathological tissues and disease states. We summarize studies of structure and nucleation of amyloid and relate these to observations on amyloid polymorphism, prion strains, coaggregation of pathogenic proteins in tissues, and mechanisms of toxicity and transmissibility. Molecular studies have also led to numerous strategies for biological and chemical interventions against amyloid diseases. © 2012 Elsevier Inc.

Alers S.,University of Tubingen | Loffler A.S.,University Hospital of Dusseldorf | Wesselborg S.,University Hospital of Dusseldorf | Stork B.,University Hospital of Dusseldorf
Cell Communication and Signaling | Year: 2012

Macroautophagy (commonly abbreviated as autophagy) is an evolutionary conserved lysosome-directed vesicular trafficking pathway in eukaryotic cells that mediates the lysosomal degradation of intracellular components. The cytoplasmic cargo is initially enclosed by a specific double membrane vesicle, termed the autophagosome. By this means, autophagy either helps to remove damaged organelles, long-lived proteins and protein aggregates, or serves as a recycling mechanism for molecular building blocks. Autophagy was once invented by unicellular organisms to compensate the fluctuating external supply of nutrients. In higher eukaryotes, it is strongly enhanced under various stress conditions, such as nutrient and growth factor deprivation or DNA damage. The serine/threonine kinase Atg1 was the first identified autophagy-related gene (ATG) product in yeast. The corresponding nematode homolog UNC-51, however, has additional neuronal functions. Vertebrate genomes finally encode five closely related kinases, of which UNC-51-like kinase 1 (Ulk1) and Ulk2 are both involved in the regulation of autophagy and further neuron-specific vesicular trafficking processes. This review will mainly focus on the vertebrate Ulk1/2-Atg13-FIP200 protein complex, its function in autophagy initiation, its evolutionary descent from the yeast Atg1-Atg13-Atg17 complex, as well as the additional non-autophagic functions of its components. Since the rapid nutrient- and stress-dependent cellular responses are mainly mediated by serine/threonine phosphorylation, it will summarize our current knowledge about the relevant upstream signaling pathways and the altering phosphorylation status within this complex during autophagy induction. © 2012 Alers et al; licensee BioMed Central Ltd.

Moustakidis C.C.,Aristotle University of Thessaloniki | Moustakidis C.C.,University of Tubingen
Physical Review C - Nuclear Physics | Year: 2012

The symmetry energy effects on the location of the inner edge of neutron star crusts are studied. Three phenomenological models are employed in order to check the accuracy of the well known parabolic approximation of the equation of state for asymmetric nuclear matter in the determination of the transition density n t and transition pressure P t. The results corroborate the statement that the error due to the assumption that a priori the equation of state is parabolic may introduce a large error in the determination of related properties of a neutron star as the crustal fraction of the moment of inertia and the critical frequency of rotating neutron stars. © 2012 American Physical Society.

Gallwitz B.,University of Tubingen
Expert Opinion on Investigational Drugs | Year: 2011

Introduction: A recent treatment advance for type 2 diabetes is the oral therapy with DPP IV inhibitors. New substances of this class are in development in order to increase alternatives for treating this important metabolic disease. The reader will gain detailed pharmacological and clinical information on alogliptin, dutogliptin and linagliptin and will learn how these DPP IV inhibitors may widen the whole drug class. Possible special indications for the various DPP IV inhibitors are discussed. Areas covered: The DPP IV inhibitors and their current role in type 2 diabetes are highlighted. Preclinical and clinical studies of the novel DPP IV inhibitors alogliptin, dutogliptin and linagliptin, including published data since 2007, are presented and a comparison of these compounds is made. Expert opinion: The efficacy and safety profile of DPP IV inhibitors are promising and advantageous so far. In contrast to sulfonylureas, DPP IV inhibitors do not have an intrinsic risk for causing hypoglycemia and they are body weight neutral. Their tolerability profile is good and no specific adverse reactions have been reported. Experience so far suggests that there are no safety issues associated with inhibition of DPP IV activity by itself. Novel DPP IV inhibitors with distinct properties may offer alternative choices within this drug class. © 2011 Informa UK, Ltd.

Satyanarayana G.,Indian Institute of Technology Hyderabad | Maier M.E.,University of Tubingen
Tetrahedron | Year: 2012

A series of 4-formyl esters 8a-d was prepared by Michael addition of an enamine with ethyl acrylate. A subsequent condensation with 2-bromobenzylamines 3 gave rise to cyclic enamides 9aa-dd. In a Heck cyclization reaction tricyclic isoindoles 10aa-dd were formed in good yields. © 2011 Elsevier Ltd. All rights reserved.

Hoenicke L.,Helmholtz Center for Infection Research | Zender L.,Helmholtz Center for Infection Research | Zender L.,Hannover Medical School | Zender L.,University of Tubingen
Carcinogenesis | Year: 2012

Cellular senescence, a state of stable growth arrest, can occur in response to various stress stimuli such as telomere shortening, treatment with chemotherapeutic drugs or the aberrant activation of oncogenes. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it has become clear that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Recent work from our laboratory showed that premalignant, senescent hepatocytes are recognized and cleared through an antigen-specific immune response and that this immune response, designated as 'senescence surveillance' is crucial for tumor suppression in the liver [(Kang,T.W. et al. (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature, 479, 547-551]. It is an emerging concept that immune responses against senescent cells have a broader biological significance in cancer- as well as non-cancer pathologies and current data suggest that distinct immune responses are engaged to clear senescent cells in different disease settings. In this review article, we will discuss different examples how immune responses against senescent cells are involved to restrict disease progression in cancer-and non-cancer pathologies. © The Author 2012. Published by Oxford University Press. All rights reserved.

Luirink J.,VU University Amsterdam | Yu Z.,VU University Amsterdam | Wagner S.,University of Tubingen | De Gier J.-W.,University of Stockholm
Biochimica et Biophysica Acta - Bioenergetics | Year: 2012

The inner membrane proteome of the model organism Escherichia coli is composed of inner membrane proteins, lipoproteins and peripherally attached soluble proteins. Our knowledge of the biogenesis of inner membrane proteins is rapidly increasing. This is in particular true for the early steps of biogenesis - protein targeting to and insertion into the membrane. However, our knowledge of inner membrane protein folding and quality control is still fragmentary. Furthering our knowledge in these areas will bring us closer to understand the biogenesis of individual inner membrane proteins in the context of the biogenesis of the inner membrane proteome of Escherichia coli as a whole. This article is part of a Special Issue entitled: Biogenesis/Assembly of Respiratory Enzyme Complexes. © 2011 Elsevier B.V.

Nonlinear effects caused by molecular association of enantiomers in non-racemic mixtures can cause unexpected effects in chiroptics, NMR spectroscopy, homogeneous catalysis, and chromatography. Herein we present a theoretical model to simulate and verify unusual elution orders of enantiomers on an achiral stationary phase doped with a small amount of a chiral selector or achiral columns coupled with columns doped with a chiral selector. Scenarios with strong, medium, and weak associations of enantiomers, different separation efficiencies typical for flash chromatography and liquid chromatography, and the influence of the enantioselectivity of the chiral selector on the complex equilibria have been investigated. The findings presented here are of importance for the validation of the determination of enantiomeric ratios in not fully separated elution zones as well as for the preparative separation of non-racemic enantiomeric mixtures on chiral stationary phases bonded to achiral matrices. © 2010 Elsevier Ltd. All rights reserved.

Ebner F.H.,University of Tubingen
Neurosurgical focus | Year: 2010

The objective of this study was to evaluate and analyze morphometric and volumetric changes of the skull due to acromegaly in areas relevant for neurosurgical practice, focusing on the surgical implications. On preoperatively acquired CT scans, cephalometric and volumetric measurements were performed on 45 patients with acromegaly (Group A) and 45 control patients (Group B). The authors determined thickness of the cranial vault, inner and outer diameters of the skull, and the diameter of sphenoidal and maxillary sinus, as well as frontal and maxillary sinus volumetry. The morphometric and volumetric CT data of the patients with acromegaly were compared with the data of a control group and correlated with clinical parameters. Cranial vault thickness differed significantly (p < 0.0001) between the 2 groups. A correlation of the vault thickness with preoperative human growth hormone, insulin-like growth factor-I levels, and duration of clinical history in acromegaly could not be established. The outer anterior-posterior skull diameter of Group A (18.47 ± 0.94 cm) differed significantly (p = 0.0146) from Group B (17.98 ± 0.93 cm) and correlated significantly with preoperative human growth hormone (r = 0.3277; p = 0.0299) and insulin-like growth factor--I serum levels (r = 0.3756; p = 0.0120). Measurements of the anterior-posterior diameter of the sphenoidal sinus differed significantly (p = 0.0074) between patients with acromegaly and controls. Volumetric analysis of the frontal sinus resulted in a statistically significant difference (p = 0.0382) between patients with acromegaly (14.89 ± 10.85 cm3) and controls (10.06 ± 6.93 cm3). Significant craniometric changes and volumetric remodelling of the paranasal sinus occur in acromegaly. The bone alterations are of surgical importance for using the transsphenoidal approach. Detailed preoperative diagnostic examination and planning as well as selection of appropriate instruments are mandatory for safe and successful pituitary adenoma removal in patients with acromegaly.

Treiber N.,Max Planck Institute of Immunobiology | Treiber T.,Max Planck Institute of Immunobiology | Zocher G.,University of Tubingen | Grosschedl R.,Max Planck Institute of Immunobiology
Genes and Development | Year: 2010

Early B-cell factor 1 (Ebf1) is a key transcriptional determinant of B-lymphocyte differentiation whose DNA-binding domain has no sequence similarity to other transcription factor families. Here we report the crystal structure of an Ebf1 dimer bound to its palindromic recognition site. The DNA-binding domain adopts a pseudoimmunoglobulin-like fold with novel topology, but is structurally similar to the Rel homology domains of NFAT and NF-κB. Ebf1 contacts the DNA with two loop-based modules and a unique Zn coordination motif whereby each Ebf1 monomer interacts with both palindromic half-sites. This unusual mode of DNA recognition generates an extended contact area that may be crucial for the function of Ebf1 in chromatin. © 2010 by Cold Spring Harbor Laboratory Press.

Strehl U.,University of Tubingen
Frontiers in Human Neuroscience | Year: 2014

Popular definitions of neurofeedback point out that neurofeedback is a process of operant conditioning which leads to self-regulation of brain activity. Self-regulation of brain activity is considered to be a skill. The aim of this paper is to clarify that not only operant conditioning plays a role in the acquisition of this skill. In order to design the learning process additional references have to be derived from classical conditioning, two-process-theory and in particular from skill learning and research into motivational aspects. The impact of learning by trial and error, cueing of behavior, feedback, reinforcement, and knowledge of results as well as transfer of self-regulation skills into everyday life will be analyzed in this paper. In addition to these learning theory basics this paper tries to summarize the knowledge about acquisition of self-regulation from neurofeedback studies with a main emphasis on clinical populations. As a conclusion it is hypothesized that learning to self-regulate has to be offered in a psychotherapeutic, i.e., behavior therapy framework. © 2014 Strehl.

Although antimicrobial peptides protect mucus and mucosa from bacteria, Helicobacter pylori is able to colonize the gastric mucus. To clarify in which extend Helicobacter escapes the antimicrobial defense, we systematically assessed susceptibility and expression levels of different antimicrobial host factors in gastric mucosa with and without H. pylori infection. We investigated the expression levels of HBD1 (gene name DEFB1), HBD2 (DEFB4A), HBD3 (DEFB103A), HBD4 (DEFB104A), LL37 (CAMP) and elafin (PI3) by real time PCR in gastric biopsy samples in a total of 20 controls versus 12 patients colonized with H. pylori. Immunostaining was performed for HBD2 and HBD3. We assessed antimicrobial susceptibility by flow cytometry, growth on blood agar, radial diffusion assay and electron microscopy. H. pylori infection was associated with increased gastric levels of the inducible defensin HBD2 and of the antiprotease elafin, whereas the expression levels of the constitutive defensin HBD1, inducible HBD3 and LL37 remained unchanged. HBD4 was not expressed in significant levels in gastric mucosa. H. pylori strains were resistant to the defensins HBD1 as well as to elafin, and strain specific minimally susceptible to HBD2, whereas HBD3 and LL37 killed all H. pylori strains effectively. We demonstrated the binding of HBD2 and LL37 on the surface of H. pylori cells. Comparing the antibacterial activity of extracts from H. pylori negative and positive biopsies, we found only a minimal killing against H. pylori that was not increased by the induction of HBD2 in H. pylori positive samples. These data support the hypothesis that gastric H. pylori evades the host defense shield to allow colonization.

Synofzik M.,University of Tubingen | Schlaepfer T.E.,University of Bonn | Schlaepfer T.E.,Johns Hopkins University
Brain Stimulation | Year: 2011

Background: Deep brain stimulation (DBS) has been used for neuropsychiatric disorders in clinical and research settings for almost 50 years now. Recent evidence demonstrates some efficacy in treating obsessive-compulsive disorder and major depression in patients refractory to other treatment modalities beyond single case reports. This has led to a considerable surge of clinical and commercial interest in DBS for psychiatric indications. Because of the high vulnerability of psychiatric patients, the lack of extensive short- and long-term data about effectiveness and the rapid spread of questionable indications this new field in psychiatry requires ethical criteria that can be applied to both research and clinical decision-making. Objective and Methods: We here present an evidence-based systematic ethical analysis of psychiatric DBS using the criteria of beneficence, nonmaleficence, and autonomy. Results and Conclusions: The proposed criteria are helpful in analyzing empirical evidence, informing research investigations and guiding clinical decision-making. This will prepare the ground for ethically justified, empirically comprehensive DBS in this highly vulnerable population and allow stringent future societal discussions about its legitimation. © 2011 Elsevier Inc. All rights reserved.

Poets C.F.,University of Tubingen
Acta Paediatrica, International Journal of Paediatrics | Year: 2010

Aim: To review treatments for apnoea of prematurity (AOP). Methods: Literature Review and description of personal practice. Results: Provided that symptomatic apnoea has been ruled out, interventions to improve AOP can be viewed as directed at one of three underlying mechanisms: (i) a reduced work of breathing [e.g. prone positioning, nasal continuous positive airway pressure (CPAP)], (ii) an increased respiratory drive (e.g. caffeine), and (iii) an improved diaphragmatic function (e.g. branched-chain amino acids). Most options currently applied, however, have not yet been shown to be effective and/or safe, except for prone, head-elevated positioning, synchronized nasal ventilation/CPAP, and caffeine. Conclusion: Treatment usually follows an incremental approach, starting with positioning, followed by caffeine (which should be started early, at least in infants <1250 g), and nasal ventilation or CPAP via variable flow systems that reduce work of breathing. From a research point of view, we most urgently need data on the frequency and severity of bradycardia and intermittent hypoxia that can yet be tolerated without putting an infant at risk of impaired development or retinopathy of prematurity. © 2009 Foundation Acta Pædiatrica.

Cerebellar cortical signals are carried to their principal target, the deep cerebellar nuclear neurons (DCNs), via the inhibitory pathway formed by Purkinje cell (PC) axons. Two different intrinsic properties of DCNs, rebound excitation and automatic firing, have been proposed to support ensuing mechanisms for information transfer via inhibitory synapses. The efficacy of these mechanisms was investigated using whole-cell recordings of spontaneously firing DCNs in cerebellar slices. Results using current injection revealed that both mechanisms are effective in spontaneously firing DCNs but operate at different ranges of membrane potential. Rebound frequency was well correlated to the duration and amplitude of the preceding hyperpolarization. Activation of PC synapses with trains of stimuli few seconds long elicited rebound firing in all tested neurons, demonstrating that inhibition can elicit rebounds in DCNs held at their spontaneous membrane potential. Rebounds could be also elicited by single stimulus in a subset of neurons. The rebound frequency was significantly correlated to the synaptic stimulus strength, supporting the idea that rebound frequency may encode the amplitude of inhibition and thus serve to transfer inhibitory signals in the cerebellar circuit. © 2010 Springer Science+Business Media, LLC.

Clement H.,University of Tubingen
Progress in Particle and Nuclear Physics | Year: 2012

The two-pion production in nucleonnucleon collisions has been investigated systematically by exclusive and kinematically complete measurements at CELSIUS/WASA and more recently at COSY-TOF and particularly WASA@COSY. The data for all pp-induced isovector production channels in the energy range from threshold up to T p = 1.4 GeV can be well understood by t-channel Roper, ΔΔ and possibly Δ(1600) excitation. In contrast to that the purely isoscalar reaction channel pn→dπ 0π 0 exhibits a narrow resonance-like structure with m=2.37GeV and Γ=70MeV in the total cross section, which is correlated with an intriguing low-mass enhancement in the ππ invariant mass spectrum (ABC effect) as well as with the formation of a ΔΔ system in the intermediate state. From the angular distributions the spin and parity of this structure have been derived resulting in I(J P)=0(3 +). The consequences of the resonance hypothesis for other reaction channels are discussed. The fact that also the double-pionic fusion reactions to 3He and 4He exhibit a corresponding resonance-like structure in the total cross section correlated with the ABC effect suggests that the underlying conjectured pn resonance is obviously robust enough to survive in nuclei. © 2012 Elsevier B.V. All rights reserved.

Gutsche T.,University of Tubingen
Progress in Particle and Nuclear Physics | Year: 2012

We discuss possible exotic structure interpretations of the scalar mesons f 0(1370), f 0(1500) and f 0(1710) and the charmonium-like state X(3872). The scalars are shown to result from a scheme where the excited quarkonia QQ configurations mix with the lowest lying glueball. Within an effective chiral Lagrangian approach the strong decays of these states are shown to be consistent within this structure assumption. We also discuss the role of the scalar resonances f 0(1370), f 0(1500) and f 0(1710) in the strong and radiative three-body decays of Jψ, presenting further tests for this scenario. The charmonium-like X(3872) is assumed to consist dominantly of molecular hadronic components with an additional small admixture of a charmonium configuration. A potential model based on meson exchange is able to generate weak binding of the molecular hadronic components. The observed radiative (γJψ and γψ(2s)) and strong (Jψ2π and Jψ3π) decays are shown to be consistent with the molecular structure assumption of the X(3872). © 2012 Elsevier B.V. All rights reserved.

Brigger D.,University of Bern | Proikas-Cezanne T.,University of Tubingen | Tschan M.P.,University of Bern
Cell Death and Disease | Year: 2014

Members of the WD-repeat protein interacting with phosphoinositides (WIPI) family are phosphatidylinositol 3-Phosphate (PI3P) effectors that are essential for the formation of autophagosomes. Autophagosomes, unique double-Membraned organelles, are characteristic for autophagy, a bulk degradation mechanism with cytoprotective and homeostatic function. Both, WIPI-1 and WIPI-2 are aberrantly expressed in several solid tumors, linking these genes to carcinogenesis. We now found that the expression of WIPI-1 was significantly reduced in a large cohort of 98 primary acute myeloid leukemia (AML) patient samples (complex karyotypes; t(8;21); t(15,17); inv(16)). In contrast, the expression of WIPI-2 was only reduced in acute promyelocytic leukemia (APL), a distinct subtype of AML (t(15,17)). As AML cells are blocked in their differentiation, we tested if the expression levels of WIPI-1 and WIPI-2 increase during all-Trans retinoic acid (ATRA)-Induced neutrophil differentiation of APL. According to the higher WIPI-1 expression in granulocytes compared with immature blast cells, WIPI-1 but not WIPI-2 expression was significantly induced during neutrophil differentiation of NB4 APL cells. Interestingly, the induction of WIPI-1 expression was dependent on the transcription factor PU.1, a master regulator of myelopoiesis, supporting our notion that WIPI-1 expression is reduced in AML patients lacking proper PU-1 activity. Further, knocking down WIPI-1 in NB4 cells markedly attenuated the autophagic flux and significantly reduced neutrophil differentiation. This result was also achieved by knocking down WIPI-2, suggesting that both WIPI-1 and WIPI-2 are functionally required and not redundant in mediating the PI3P signal at the onset of autophagy in NB4 cells. In line with these data, downregulation of PI3KC3 (hVPS34), which generates PI3P upstream of WIPIs, also inhibited neutrophil differentiation. In conclusion, we demonstrate that both WIPI-1 and WIPI-2 are required for the PI3Pdependent autophagic activity during neutrophil differentiation, and that PU.1-Dependent WIPI-1 expression is significantly repressed in primary AML patient samples and that the induction of autophagic flux is associated with neutrophil differentiation of APL cells. © 2014 Macmillan Publishers Limited All rights reserved 2041-4889/14.

Wolburg H.,University of Tubingen | Paulus W.,University of Munster
Acta Neuropathologica | Year: 2010

The choroid plexus is an epithelial-endothelial vascular convolute within the ventricular system of the vertebrate brain. It consists of epithelial cells, fenestrated blood vessels, and the stroma, dependent on various physiological or pathological conditions, which may contain fibroblasts, mast cells, macrophages, granulocytes or other infiltrates, and a rich extracellular matrix. The choroid plexus is mainly involved in the production of cerebrospinal fluid (CSF) by using the free access to the blood compartment of the leaky vessels. In order to separate blood and CSF compartments, choroid plexus epithelial cells and tanycytes of circumventricular organs constitute the blood-CSF-brain barrier. As non-neuronal cells in the brain and derived from neuroectoderm, choroid plexus epithelia are defined as a subtype of macroglia. The choroid plexus is involved in a variety of neurological disorders, including neurodegenerative, inflammatory, infectious, traumatic, neoplastic, and systemic diseases. Aβ and Biondi ring tangles accumulate in the Alzheimer's disease choroid plexus. In multiple sclerosis, the choroid plexus could represent a site for lymphocyte entry in the CSF and brain, and for presentation of antigens. Recent studies have provided new diagnostic markers and potential molecular targets for choroid plexus papilloma and carcinoma, which represent the most common brain tumors in the first year of life. We here revive some of the classical studies and review recent insight into the biology and pathology of the choroid plexus. © 2009 Springer-Verlag.

Huber M.,University of Tubingen
Journal of Combinatorial Theory. Series A | Year: 2011

Graphs with high symmetry or regularity are the main source for experimentally hard instances of the notoriously difficult graph isomorphism problem. In this paper, we study the computational complexity of isomorphism testing for line graphs of t-(v,k,λ) designs. For this class of highly regular graphs, we obtain a worst-case running time of O(vlogv+O(1)) for bounded parameters t, k, λ. In a first step, our approach makes use of the Babai-Luks algorithm to compute canonical forms of t-designs. In a second step, we show that t-designs can be reconstructed from their line graphs in polynomial-time. The first is algebraic in nature, the second purely combinatorial. For both, profound structural knowledge in design theory is required. Our results extend earlier complexity results about isomorphism testing of graphs generated from Steiner triple systems and block designs. © 2010 Elsevier Inc.

Huillet T.,Cergy-Pontoise University | Mohle M.,University of Tubingen
Theoretical Population Biology | Year: 2013

We study the asymptotics of the extended Moran model as the total population size N tends to infinity. Two convergence results are provided, the first result leading to discrete-time limiting coalescent processes and the second result leading to continuous-time limiting coalescent processes. The limiting coalescent processes allow for multiple mergers of ancestral lineages (Λ-coalescent). It is furthermore verified that any continuous time Λ-coalescent (with Λ any probability distribution) can arise in the limit. Typical examples of extended Moran models are discussed, with an emphasis on models being in the domain of attraction of beta coalescents or Λ-coalescents with Λ being log infinitely divisible. © 2011 Elsevier Inc.

Bieri O.,University of Basel | Scheffler K.,Max Planck Institute for Biological Cybernetics | Scheffler K.,University of Tubingen
Journal of Magnetic Resonance Imaging | Year: 2013

Balanced steady state free precession (balanced SSFP) has become increasingly popular for research and clinical applications, offering a very high signal-to-noise ratio and a T2/T1-weighted image contrast. This review article gives an overview on the basic principles of this fast imaging technique as well as possibilities for contrast modification. The first part focuses on the fundamental principles of balanced SSFP signal formation in the transient phase and in the steady state. In the second part, balanced SSFP imaging, contrast, and basic mechanisms for contrast modification are revisited and contemporary clinical applications are discussed. © 2013 Wiley Periodicals, Inc.

Kleindienst S.,University of Georgia | Kleindienst S.,University of Tubingen | Paul J.H.,University of South Florida | Joye S.B.,University of Georgia
Nature Reviews Microbiology | Year: 2015

Dispersants are globally and routinely applied as an emergency response to oil spills in marine ecosystems with the goal of chemically enhancing the dissolution of oil into water, which is assumed to stimulate microbially mediated oil biodegradation. However, little is known about how dispersants affect the composition of microbial communities or their biodegradation activities. The published findings are controversial, probably owing to variations in laboratory methods, the selected model organisms and the chemistry of different dispersant-oil mixtures. Here, we argue that an in-depth assessment of the impacts of dispersants on microorganisms is needed to evaluate the planning and use of dispersants during future responses to oil spills.

Hailfinger S.,University of Tubingen | Lenz G.,Charite - Medical University of Berlin | Thome M.,University of Lausanne
Current Opinion in Chemical Biology | Year: 2014

The paracaspase MALT1 is an Arg-specific protease that cleaves multiple substrates to promote lymphocyte proliferation and survival. The catalytic activity of MALT1 is normally tightly regulated by antigen receptor triggering, which promotes MALT1 activation by its inducible monoubiquitination-dependent dimerization. Constitutive MALT1 activity is a hallmark of specific subsets of B-cell lymphomas, which are characterized by chromosomal translocations or point mutations that activate MALT1 or its upstream regulators. Recent findings suggest that such lymphomas may be sensitive to treatment with MALT1 inhibitors. Here we review recent progress in the understanding of MALT1 function and regulation, and the development of small molecule MALT1 inhibitors for therapeutic applications. © 2014 Elsevier Ltd.

Bodemer D.,University of Tubingen | Dehler J.,University of Fribourg
Computers in Human Behavior | Year: 2011

Group awareness is an emerging topic in research on computer-supported collaborative learning (CSCL). It covers the knowledge and perception of behavioral, cognitive, and social context information on a group or its members. A central aim of CSCL-related research on group awareness is the development of tools that implicitly guide learners' behavior, communication, and reflection by the presentation of information on a learning partner or a group. This special issue comprises six empirical contributions and a concluding discussion that present a broad spectrum of current research on this topic including behavioral, cognitive and social group awareness. An introductory outline of how group awareness is formed, processed and translated in action along the contributions is intended to integrate the diverse research activities on group awareness in CSCL environments. © 2010 Elsevier Ltd. All rights reserved.

Nahnsen S.,University of Tubingen
BMC bioinformatics | Year: 2012

Selected reaction monitoring (SRM)-based proteomics approaches enable highly sensitive and reproducible assays for profiling of thousands of peptides in one experiment. The development of such assays involves the determination of retention time, detectability and fragmentation properties of peptides, followed by an optimal selection of transitions. If those properties have to be identified experimentally, the assay development becomes a time-consuming task. We introduce a computational framework for the optimal selection of transitions for a given set of proteins based on their sequence information alone or in conjunction with already existing transition databases. The presented method enables the rapid and fully automated initial development of assays for targeted proteomics. We introduce the relevant methods, report and discuss a step-wise and generic protocol and we also show that we can reach an ad hoc coverage of 80 % of the targeted proteins. The presented algorithmic procedure is implemented in the open-source software package OpenMS/TOPP.

Konig M.,Charite - Medical University of Berlin | Drager A.,University of Tubingen | Holzhutter H.-G.,Charite - Medical University of Berlin
Bioinformatics | Year: 2012

Summary: CySBML is a plugin designed to work with Systems Biology Markup Language (SBML) in Cytoscape having the following features: SBML import, support of the SBML layout and qualitative model packages, navigation in network layouts based on SBML structure, access to MIRIAM and SBO-based annotations and SBML validation. CySBML includes an importer for BioModels to load SBML from standard repositories. © The Author 2012. Published by Oxford University Press. All rights reserved.

Muller L.,Max Planck Institute for Human Development | Pawelec G.,University of Tubingen
Brain, Behavior, and Immunity | Year: 2014

Immune responses to pathogens to which they were not previously exposed are commonly less effective in elderly people than in young adults, whereas those to agents previously encountered and overcome in earlier life may be amplified. This is reflected in the robust finding in many studies that the proportions and numbers of naïve B and T cells are lower and memory cells higher in the elderly. In addition to the "extrinsic" effects of pathogen exposure, "intrinsic" events such as age-associated differences in haematopoeitic stem cells and their niches in the bone marrow associated with differences in cell maturation and output to the periphery are also observed. In the case of T cells, the "intrinsic" process of thymic involution, beginning before puberty, further contributes to reducing the production of naïve T cells. Like memory T cell populations, innate immune cells may be increased in number but decreased in efficacy on a per-cell basis. Thus, superimposed on chronological age alone, remodelling of immunity as a result of interactions with the environment over the life course is instrumental in shaping immune status in later life. In addition to interactions with pathogens, host microbiome and nutrition, exercise and stress, and many other extrinsic factors are crucial modulators of this "immunosenescence" process. In this review, we briefly outline the observed immune differences between younger and older people, and discuss the possible impacts of behavioral variations thereon. © 2013 Elsevier Inc.

Bettinger H.F.,University of Tubingen
Angewandte Chemie - International Edition | Year: 2010

(Chemical Equation Presentation) A molecule on a slipery slope: Lineberger et al. finally managed to observe the oxyallyl diradical 1 using negative ion photoelectron spectroscopy. The singlet state of the oxyallyl diradical is lower in energy than the triplet and corresponds to the transition state for ring closure to cyclopropanone 2. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Strikman M.,Pennsylvania State University | Vogelsang W.,University of Tubingen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2011

We estimate the contributions by double-parton interactions to the cross sections for pp→π0π0X and dA→π0π0X at the Relativistic Heavy Ion Collider (RHIC). We find that such contributions become important at large forward rapidities of the produced pions. This is, in particular, the case for dA scattering, where they strongly enhance the azimuthal-angular independent pedestal component of the cross section, providing a natural explanation of this feature of the RHIC dA data. We argue that the discussed processes open a window to studies of double quark distributions in nucleons. We also briefly address the roles of shadowing and energy loss in dA scattering, which we show to affect the double-inclusive pion cross section much more strongly than the single-inclusive one. We discuss the implications of our results for the interpretation of pion azimuthal correlations. © 2011 American Physical Society.

Grimme S.,University of Bonn | Goerigk L.,University of Sydney | Fink R.F.,University of Tubingen
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2012

Spin-component-scaled (SCS) electron correlation methods for electronic structure theory are reviewed. The methods can be derived theoretically by applying special conditions to the underlying wave functions in perturbation theory. They are based on the insight that low-order wave function expansions treat the correlation effects of electron pairs with opposite spin (OS) and same spin (SS) differently because of their different treatment at the underlying Hartree-Fock level. Physically, this is related to the different average inter-electronic distances in the SS and OS electron pairs. The overview starts with the original SCS-MP2 method and discusses its strengths and weaknesses and various ways to parameterize the scaling factors. Extensions to coupled-cluster and excited state methods as well the connection to virtual-orbital dependent density functional approaches are highlighted. The performance of various SCS methods in large thermochemical benchmarks and for excitation energies is discussed in comparison with other common electronic structure methods. © 2012 John Wiley & Sons, Ltd.

BACKGROUND:: Liver ischemia/reperfusion (IR) injury is characterized by hepatic tissue damage and an inflammatory response. This is accompanied by the formation and vascular sequestration of platelet–neutrophil conjugates (PNCs). Signaling through Adora2b adenosine receptors can provide liver protection. Volatile anesthetics may interact with adenosine receptors. This study investigates potential antiinflammatory effects of the volatile anesthetic sevoflurane during liver IR. METHODS:: Experiments were performed ex vivo with human blood and in a liver IR model with wild-type, Adora2a, and Adora2b mice. The effect of sevoflurane on platelet activation, PNC formation and sequestration, cytokine release, and liver damage (alanine aminotransferase release) was analyzed using flow cytometry, luminometry, and immunofluorescence. Adenosine receptor expression in liver tissue was analyzed using immunohistochemistry and real-time polymerase chain reaction. RESULTS:: Ex vivo experiments indicate that sevoflurane inhibits platelet and leukocyte activation (n = 5). During liver IR, sevoflurane (2 Vol%) decreased PNC formation 2.4-fold in wild-type (P < 0.05) but not in Adora2b mice (n ≥ 5). Sevoflurane reduced PNC sequestration 1.9-fold (P < 0.05) and alanine aminotransferase release 3.5-fold (P < 0.05) in wild-type but not in Adora2b mice (n = 5). In Adora2a mice, sevoflurane also inhibited PNC formation and cytokine release. Sevoflurane diminished cytokine release (n ≥ 3) and increased Adora2b transcription and expression in liver tissue of wild-types (n = 4). CONCLUSIONS:: Our experiments highlight antiinflammatory and tissue-protective properties of sevoflurane during liver IR and reveal a mechanistic role of Adora2b in sevoflurane-associated effects. The targeted use of sevoflurane not only as an anesthetic but also to prevent IR damage is a promising approach in the treatment of critically ill patients. Copyright © by 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.

Monoclonal antibodies directed to the B-cell-specific CD20-antigen are successfully used for the treatment of lymphomas and autoimmune diseases. Here, we compare the anti-B-cell activity of three different antibodies directed to CD20: (i) a chimeric, monospecific antibody, (ii) an Fc-optimized variant thereof, and (iii) a bispecific CD20×CD95-antibody in a newly developed recombinant format, termed Fabsc. The bispecific antibody specifically triggers the CD95 death receptor on malignant, as well as activated, normal B-cells. We found that the capability of this antibody to suppress the growth of malignant B-cells in vitro and in vivo and to specifically deplete normal, activated B-cells from peripheral blood mononuclear cell (PBMC) cultures was superior to that of the Fc-optimized monospecific antibody. This antibody in turn was more effective than its nonoptimized variant. Moreover, the bispecific antibody was the only reagent capable of significantly suppressing antibody production in vitro. Our findings imply that the bispecific CD20×CD95-antibody might become a new, prototypical reagent for the treatment of B-cell-mediated autoimmune disease.Molecular Therapy (2015); doi:10.1038/mt.2015.209. © 2015 American Society of Gene & Cell Therapy

Verschoor A.,TU Munich | Langer H.F.,University of Tubingen
Thrombosis and Haemostasis | Year: 2013

Platelets have a central function in repairing vascular damage and stopping acute blood loss. They are equally central to thrombus formation in cardiovascular diseases such as myocardial infarction and ischaemic stroke. Beyond these classical prothrombotic diseases, immune mediated pathologies such as haemolytic uraemic syndrome (HUS) or paroxysmal nocturnal haemoglobinuria (PNH) also feature an increased tendency to form thrombi in various tissues. It has become increasingly clear that the complement system, part of the innate immune system, has an important role in the pathophysiology of these diseases. Not only does complement influence prothrombotic disease, it is equally involved in idiopathic thrombocytopenic purpura (ITP), an autoimmune disease characterised by thrombocytopenia. Thus, there are complex interrelationships between the haemostatic and immune systems, and platelets and complement in particular. Not only does complement influence platelet diseases such as ITP, HUS and PNH, it also mediates interaction between microbes and platelets during systemic infection, influencing the course of infection and development of protective immunity. This review aims to provide an integrative overview of the mechanisms underlying the interactions between complement and platelets in health and disease. © Schattauer 2013.

UDP-glucuronosyltransferases (UGTs) catalyze a major Phase II reaction in the endo- and xenobiotic-metabolizing enzyme (XME) system consisting of Phases I-III proteins and ligand-activated transcription factors. Differential induction of liver microsomal CYP activities following treatment of rats with aryl hydrocarbons or phenobarbital, discovered over 50 years ago, initiated studies to characterize multiple CYPs and the transcription factors Ah receptor (AhR) and CAR, respectively. Similar studies of UGT activities initiated studies of multiple UGTs. However, inducible human UGTs differed from those in rats. In addition, induction of UGTs is complicated, for example, by coordinate regulation of some XMEs by AhR and the antioxidant Nrf2 transcription factor. Functions of UGTs in the XME system are discussed using the following examples: (i) Tight coupling between Phase I and II enzymes in benzo[a]pyrene detoxification. In particular, AhR- and Nrf2-controlled quinone reductases and UGTs may prevent quinone-quinol redox cycling with generation of oxidative stress. (ii) CAR-mediated induction of UGT1A1 may be involved in perinatal detoxification of bilirubin neurotoxicity. (iii) PPARα-mediated glucuronidation of eicosanoids may contribute to their detoxification and homeostasis. Identification of the role of UGTs is challenged by intense crosstalk of transcription factors at the genetic level, the level of protein-protein interaction and control by signaling networks. Nevertheless, as drug targets ligand-activated transcription factors provide promising therapeutic possibilities. © 2011 Elsevier Inc. All rights reserved.

Despite substantial advances in the field, particularly resulting from physio- logical studies in animals, the neural mechanisms underlying the generation of many motor behaviors in humans remain unclear. A recent study (Cappellini G et al. J Neurophysiol 104: 3064-3073, 2010) sheds more light on this topic. Like the string of a violin, the -motoneuron pools in the spinal cord during locomotion show continuous and oscillatory patterns of activation. In this report, the implications and relevance of this finding are discussed in a general framework that includes neurophysiology, optimal control theory, and robotics.© 2011 by the American Physiological Society.

Proikas-Cezanne T.,University of Tubingen | Robenek H.,University of Munster
Journal of Cellular and Molecular Medicine | Year: 2011

Autophagy defines the lifespan of eukaryotic organisms by ensuring cellular survival through regulated bulk clearance of proteins, organelles and membranes. Pathophysiological consequences of improper autophagy give rise to a variety of age-related human diseases such as cancer and neurodegeneration. Rational therapeutic implementation of autophagy modulation remains problematic, as fundamental molecular details such as the generation of autophagosomes, unique double-membrane vesicles formed to permit the process of autophagy, are insufficiently understood. Here, freeze-fracture replica immunolabelling reveals WD-repeat protein interacting with phosphoinositides 1 and 2 (WIPI-1 and WIPI-2) as membrane components of autophagosomes and the plasma membrane (PM). In addition, WIPI-1 is also present in membranes of the endoplasmic reticulum (ER) and WIPI-2 was further detected in membranes close to the Golgi cisternae. Our results identify WIPI-1 and WIPI-2 as novel protein components of autophagosomes, and of membrane sites from which autophagosomes might originate (ER, PM, Golgi area). Hence therapeutic modulation of autophagy could involve approaches that functionally target human WIPI proteins. © 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

To succeed in academia, non-tenured researchers aim to maximize their quality-adjusted research output. This paper analyzes if and how changing institutional affiliations as a non-tenured post-doctoral researcher influences publications, and how potential effects depend on the context of the researcher. Theoretically, moving to another university at another place can have positive and negative effects on career success. On the one hand when moving to another institution one stands to gain knowledge (human capital), colleagues and coauthors (social capital). On the other hand part of one's knowledge might no longer be relevant and contacts to colleagues and even coauthors might be lost. In line with the latter arguments, matching analysis of an extensive dataset of German-speaking economists and management researchers reveals a short-term negative effect on publications across contexts. Examining the researchers' contexts reveals that this negative effect of mobility seems to be driven by researchers with social capital (i.e. coauthors or colleagues) tied to the doctorate granting institution. © 2015 Elsevier B.V. All rights reserved.

Gallwitz B.,University of Tubingen
Clinical Medicine Insights: Endocrinology and Diabetes | Year: 2012

Incretin based therapies have been introduced into the treatment options of type 2 diabetes a few years ago. Among them, the orally active DPP-4 inhibitors have established themselves as insulinotropic agents. Their advantage is the glucose-dependent insulinotropic action without an intrinsic risk for causing hypoglycemia. Additionally DPP-4 inhibitors have a glucose dependent glucagonostatic action contributing to improved glucose control. They are weight neutral and show a good safety and tolerability profile with comparable efficacy to sulfonylureas. Linagliptin is a novel DPP-4 inhibitor with a distinct pharmacological profile. In contrast to the other approved DPP-4 inhibitors it is eliminated by a hepatic/biliary route rather than a renal route. Therefore no dose adjustment is recommended in patients with type 2 diabetes and renal impairment. In clinical studies, it has been shown to be non-inferior to sulfonylurea treatment regarding glycemic parameters, but to possess favourable safety advantages regarding hypoglycemia frequency, body weight development and effects on cardioavascular parameters. This article gives an overview on the pharmacology of linagliptin as well as on the clinical data available. © the author(s), publisher and licensee Libertas Academica Ltd.

To optimize water use efficiency, plants regulate stomatal closure through a complex signaling process. Hydrogen peroxide (H2O2) is produced in response to several environmental stimuli, and has been identified as a key second messenger involved in the regulation of stomatal aperture. The Arabidopsis histidine kinase 5 (AHK5) has been shown to regulate stomatal closure in response to H2O2 and other stimuli that depend on H2O2. AHK5 is a member of the two-component system (TCS) in Arabidopsis. The plant TCS comprises three different protein types: the hybrid histidine kinases (HKs), the phosphotransfer proteins (HPs) and the response regulators (RRs). Here we determined TCS elements involved in H2O2- and ethylene-dependent stomatal closure downstream of AHK5. By yeast and in planta interaction assays and functional studies, AHP1, 2 and 5 as well as the response regulators ARR4 and ARR7 were identified acting downstream of AHK5 in the ethylene and H2O2 response pathways of guard cells. Furthermore, we demonstrate that aspartate phosphorylation of ARR4 is only required for the H2O2- but not for the ethylene-induced stomatal closure response. Our data suggest the presence of a complex TCS signaling network comprising of at least AHK5, several AHPs and response regulators, which modulate stomatal closure in response to H2O2 and ethylene.

Jensen-Jarolim E.,University of Veterinary Medicine Vienna | Pawelec G.,University of Tubingen
Cancer Immunology, Immunotherapy | Year: 2012

Many intriguing relationships between allergy and cancer continue to pose important unanswered questions. Is there a correlation between IgE and atopy, and cancer? Which are the most important IgE effector cells and do they inhibit or promote tumor growth? Will IgEmediated antigen uptake and cross-presentation by DCs activate CTLs or Tregs? What animal models are useful in this context and should we design specific anti-tumor immunotherapies, active or passive, based on IgE? Recombinant IgE has already been generated against the tumor-associated antigens folate-binding receptor, HER-2 and EGFR-how to exclude the risk of anaphylaxis in passive immunotherapy with IgE? How can we deal with hypersensitivity to antineoplastic drugs? What is the role of chemotherapeutics and biologicals in the modulation of IgE responses and the impact of the aberrant expression of mutated enzyme AID in cancer tissue? In an effort to survey the state-of-the-art in this area and to answer some of these questions, we invited leaders in the field to participate in a "Symposium-in- Writing". This represents a collection of peer-reviewed papers covering each group's specialist area of expertise. In this way, we aim to target the most important topics in these areas and to provide a comprehensive view of the state-of-the-art in the emerging multi-disciplinary field of "AllergoOncology". © Springer-Verlag 2012.

The behavior of adult-born cells can be easily monitored in cell culture or in lower model organisms, but longitudinal observation of individual mammalian adult-born cells in their native microenvironment still proves to be a challenge. Here we have established an approach named optical cell positioning system for long-term in vivo single-cell tracking, which integrates red-green-blue cell labeling with repeated angiography. By combining this approach with in vivo two-photon imaging technique, we characterized the in vivo migration patterns of adult-born neurons in the olfactory bulb. In contrast to the traditional view of mere radial migration of adult-born cells within the bulb, we found that juxtaglomerular cells switch from radial migration to long distance lateral migration upon arrival in their destination layer. This unique long-distance lateral migration has characteristic temporal (stop-and-go) and spatial (migratory, unidirectional or multidirectional) patterns, with a clear cell age-dependent decrease in the migration speed. The active migration of adult-born cells coincides with the time period of initial fate determination and is likely to impact on the integration sites of adult-born cells, their odor responsiveness, as well as their survival rate.Cell Research advance online publication 13 May 2016; doi:10.1038/cr.2016.55. © 2016 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences

Hadeler K.P.,University of Tubingen
Journal of Mathematical Biology | Year: 2013

Introducing quiescent phases into dynamical systems and ecological models tends to stabilize equilibria against the onset of oscillations and also to lower the amplitudes of existing periodic orbits. However, these effects occur when all interacting species go quiescent with the same rates and return to activity with the same rates. On the other hand, if the species differ with respect to these rates, then an equilibrium may even be destabilized. At least in the case of two interacting species this bifurcation phenomenon is closely related to the well-known Turing instability. In particular, for two species it is true that an equilibrium can be destabilized by quiescent phases if and only if it is excitable in the Turing sense. These effects are thoroughly studied and exhibited at the example of classical ecological models and epidemic models. Similar effects occur in delay equations and reaction-diffusion equations. The effect of stabilization against oscillations by quiescent phases can be shown as a special realization of a general principle saying that spatial heterogeneity stabilizes. The results on local stability of stationary points can be extended to periodic orbits. In particular, a geometric argument on the flow along a periodic orbit explains why convex periodic orbits, as observed in numerical simulations, tend to shrink when quiescent phases are introduced. © 2012 Springer-Verlag.

Zrenner E.,University of Tubingen
Science Translational Medicine | Year: 2013

There is no approved cure for blindness caused by degeneration of the photoreceptor cells of the retina. However, there has been encouraging progress with attempts to restore vision using microelectronic retinal implant devices. Yet many questions remain to be addressed. Where is the best location to implant multielectrode arrays? How can spatial and temporal resolution be improved? What are the best ways to ensure the safety and longevity of these devices? Will color vision be possible? This Perspective discusses the current state of the art of retinal implants and attempts to address some of the outstanding questions.

Initially, the article gives a short overview over the expansions of preventive detention the legislator has made in recent years. Secondly, prosecution statistics as well as statistics on enforcement of sentences are analyzed focusing on the effects the change in legislation has on the number and structure of preventive detainees. Hereafter, the author presents the central results of an own study titled 'Reconviction of Dangerous Recidivists'. These results further the conclusion that there is a considerable amount of persons falsely classified as dangerous amongst today's preventive detainees. © Springer-Verlag 2009.

Cipora K.,Jagiellonian University | Nuerk H.-C.,University of Tubingen | Nuerk H.-C.,Knowledge Media Research Center
Quarterly Journal of Experimental Psychology | Year: 2013

The SNARC (spatial-numerical association of response codes) described that larger numbers are responded faster with the right hand and smaller numbers with the left hand. It is held in the literature that arithmetically skilled and nonskilled adults differ in the SNARC. However, the respective data are descriptive, and the decisive tests are nonsignificant. Possible reasons for this nonsignificance could be that in previous studies (a) very small samples were used, (b) there were too few repetitions producing too little power and, consequently, reliabilities that were too small to reach conventional significance levels for the descriptive skill differences in the SNARC, and (c) general mathematical ability was assessed by the field of study of students, while individual arithmetic skills were not examined. Therefore we used a much bigger sample, a lot more repetitions, and direct assessment of arithmetic skills to explore relations between the SNARC effect and arithmetic skills. Nevertheless, a difference in SNARC effect between arithmetically skilled and nonskilled participants was not obtained. Bayesian analysis showed positive evidence of a true null effect, not just a power problem. Hence we conclude that the idea that arithmetically skilled and nonskilled participants generally differ in the SNARC effect is not warranted by our data. © 2013 The Experimental Psychology Society.

Ehrlich S.,University of Bonn | Bettinger H.F.,University of Tubingen | Grimme S.,University of Bonn
Angewandte Chemie - International Edition | Year: 2013

The σ-bonded butterfly structure of the nonacene dimer shows unusual dispersion-driven conformational isomerism that is due to strong intramolecular dispersion interactions between the wings of annulated aromatic rings. High-level LPNO-CEPA and DFT-D3 ab initio calculations are in good mutual agreement, whereas dispersion-devoid DFT and the MP2 method completely fail. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Boch J.,Martin Luther University of Halle Wittenberg | Bonas U.,Martin Luther University of Halle Wittenberg | Lahaye T.,University of Tubingen
New Phytologist | Year: 2014

Summary: Transcription activator-like effectors (TALEs) from plant pathogenic Xanthomonas spp. and the related RipTALs from Ralstonia solanacearum are DNA-binding proteins with a modular DNA-binding domain. This domain is both predictable and programmable, which simplifies elucidation of TALE function in planta and facilitates generation of DNA-binding modules with desired specificity for biotechnological approaches. Recently identified TALE host target genes that either promote or stop bacterial disease provide new insights into how expression of TALE genes affects the plant-pathogen interaction. Since its elucidation the TALE code has been continuously refined and now provides a mature tool that, in combination with transcriptome profiling, allows rapid isolation of novel TALE target genes. The TALE code is also the basis for synthetic promoter-traps that mediate recognition of TALE or RipTAL proteins in engineered plants. In this review, we will summarize recent findings in plant-focused TALE research. In addition, we will provide an outline of the newly established gene isolation approach for TALE or RipTAL host target genes with an emphasis on potential pitfalls. © 2014 New Phytologist Trust.

Zhang C.,CAS Institute of Geology and Geophysics | Appel E.,University of Tubingen | Qiao Q.,CAS Institute of Geology and Geophysics
Geophysical Journal International | Year: 2013

The presence of heavy metals (HMs) in the environment is a major threat for humans. Magnetic proxies provide a rapid method for assessing the degree of HM pollution in environment. We have studied farmland soil irrigated with polluted river water in the vicinity of a steel plant in Loudi city (Hunan Province, China) to test the efficiency of magnetic methods for detecting the degree ofHMpollution. Both magnetic and non-magnetic (microscopic, chemical and statistical) methods were used to characterize these farmland soils. Enhanced magnetic concentration values were found in the upper arable soil horizon (0-20 cm), which is related to the presence of spherical ̃10 to 30 μm sized magnetite particles. The spatial distribution of magnetic concentration andHMcontents in the farmland soils matches with the spatial pattern of these parameters in river sediments. These findings provide evidence that HM pollution of the farmland soil is mainly caused by irrigation with wastewater. HMs Zn, Pb, Cu, Cd, Co, Ni, V are well correlate with magnetic susceptibility (χ). The pollution load index (PLI) of all nine anthropogenic HMs (including also Cr and Mo) and log10(χ) are significantly correlated. Using the resulting linear PLI-log10(χ) function, values of χ can serve as a convenient tool for semi-quantifying the degree of HMpollution in the uppermost̃20 cm of the studied farmland soils. These findings suggest that magnetic methods can generally serve as a convenient tool for detecting and mapping HM pollution in farmland soil irrigated with wastewater from sites nearby heavy industrial activities. © The Authors 2012. Published by Oxford University Press on behalf of The Royal Astronomical Society.

Schubring A.,Gothenburg University | Thiel A.,University of Tubingen
Sociology of Sport Journal | Year: 2014

Growing up in elite sport represents a challenging project. Young athletes must negotiate a career-defining transitional period while in the midst of adolescence. In this context, notably, the growth process can lead to health problems such as overloading and injuries. In this article, we investigate how adolescent elite athletes cope with problematic growth experiences. Taking a Bourdieusian perspective, we consider coping to be a socioculturally-located practice. Drawing on qualitative interviews and participant observation in German elite sport, our conversational analysis reveals five typical coping strategies among young athletes: (a) distancing, (b) rationalization, (c) active agency, (d) self-disciplining, and (e) responsibility transfer. We reflect on the health-compromising side effects of these strategies as well as the implications for the sporting community's handling of growth problems.

Luo J.,Georgia Institute of Technology | Cirpka O.A.,University of Tubingen
Water Resources Research | Year: 2011

Macroscopic transport models calibrated by flux-averaged breakthrough curves of conservative compounds do not necessarily characterize mixing well because such breakthrough curves do not provide information on fluctuations of concentration within the solute flux, which may influence mean reaction rates. We numerically examine the validity of macroscopic transport models, which are capable of describing all details of flux-averaged breakthrough curves, for predicting a mixing-controlled bimolecular precipitation reaction in heterogeneous media. We consider a homogeneous, isotropic medium with an elliptical, low-permeability inclusion and random heterogeneous fields. For the single-inclusion case, slow advection through the inclusion results in a multimodal breakthrough curve with enhanced tailing. We vary the hydraulic conductivity contrast and Peclet number to investigate the performance of a "perfect" macroscopic transport model for predicting the total precipitated mass within the domain and the peak concentration difference between the conservative and reactive cases at the outflow boundary. The results indicate that such a model may perform well in media with either very small or very high permeability contrast or at low Peclet number. In the high-contrast case, most flow takes place in preferential flow paths, resulting in a small variance of the flux-weighted concentration, even though the offset in the breakthrough between the slow and fast travel paths is substantial. Maximum relative errors in terms of total precipitated mass and the peak concentration difference between the conservative and reactive cases occur at intermediate permeability contrasts and large Peclet numbers. Numerical simulations on random heterogeneous fields confirm the finding of the single-inclusion case. Thus, in cases with intermediate hydraulic conductivity contrast, making macroscopic models fit flux-averaged concentration breakthrough curves better may not improve the prediction of mixing-controlled reactive transport, and it becomes necessary to quantify and account for the variability of conservative concentrations in the flux in order to formulate an appropriate macroscopic transport model that predicts mixing-controlled reactive transport. Copyright 2011 by the American Geophysical Union.

Wachter A.,University of Tubingen
RNA Biology | Year: 2010

The discovery of metabolite-sensing RNA domains with gene regulatory functions, so-called riboswitches, has greatly expanded our view of the structural and functional complexity of RNA. Hitherto, more than 20 distinct riboswitch classes have been identified, which respond to a variety of small molecules and perform sophisticated gene regulatory tasks. Riboswitches are typically positioned in the 5′ untranslated region of bacterial mRNAs, where they control gene expression by transcriptional or translational attenuation. However, the recent investigation of additional riboswitch classes has revealed a more complex repertoire of regulatory mechanisms. This also includes splicing control in filamentous fungi, green algae and higher plants by thiamin pyrophosphate-binding riboswitches, the only class of metabolite-sensing RNAs identified in eukaryotes so far. All eukaryotic riboswitches characterized to date modulate, in a first step, splicing, but the downstream processes under control vary fundamentally among different species further highlighting the versatility of this gene regulatory mechanism. © 2010 Landes Bioscience.

Knoll B.,University of Tubingen
Biological Chemistry | Year: 2010

The traditional view of cellular actin is a rather autarkic cytoskeletal framework function confined to the cytoplasm. However, there is now evidence that alterations in actin dynamics are sensed by the nucleus and subsequently modulate gene expression. In communicating with the nucleus, cytoplasmic, and most likely also nucleus-resident actin, provides a further (gene) regulatory loop to cell motility. A transcription module composed of MRTF (myocardin-related transcription factor) and SRF (serum response factor) emerges as prime target of such actin signaling. Here, I focus on the nervous system, where the actin-MRTF-SRF entity governs multiple aspects of neuronal motility. © by Walter de Gruyter · Berlin · New York.

Olson E.N.,University of Texas Southwestern Medical Center | Nordheim A.,University of Tubingen
Nature Reviews Molecular Cell Biology | Year: 2010

Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actinĝ€"MRTFĝ€"SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity. © 2010 Macmillan Publishers Limited. All rights reserved.

Smolnikov A.,Max Planck Institute for Nuclear Physics | Grabmayr P.,University of Tubingen
Physical Review C - Nuclear Physics | Year: 2010

The Germanium Detector Array (GERDA) collaboration will be searching for neutrinoless double β decay of Ge76. As a result it will measure the half-life T1/2 of this rare process; or at least a new value for the lower limit for T1/2 will be derived. The sensitivity of the GERDA experiment on the effective electron neutrino mass ββ depends on the theoretical value for the nuclear matrix element M and the kinematical phase space factor G. In this Brief Report we focus on existing difficulties in applying the dimensionless values of M calculated by various theoretical groups, which use different methods and parametrizations. The implicit radius dependencies in M and G are discussed. Resulting values of the neutrino mass are tabulated for various representative half-lives T1/2 representing the sensitivity of the various phases of the GERDA experiment. © 2010 The American Physical Society.

Simkovic F.,Comenius University | Vergados J.,University of Ioannina | Faessler A.,University of Tubingen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2010

It is well known that there exist many mechanisms that may contribute to neutrinoless double beta decay. By exploiting the fact that the associated nuclear matrix elements are target dependent we show that, given definite experimental results on a sufficient number of targets, one can determine or sufficiently constrain all lepton violating parameters including the mass term. As a specific example we show that, assuming the observation of the 0νββ decay in three different nuclei, e.g., Ge76, Mo100, and Te130, and just three lepton number violating mechanisms (light- and heavy-neutrino mass mechanisms as well as the R-parity breaking supersymmetry mechanism) being active, there are only four different solutions for the lepton violating parameters, provided that they are relatively real. In particular, our analysis shows that the effective neutrino Majorana mass |mββ| can be almost uniquely extracted by utilizing other existing constraints (cosmological observations and tritium β-decay experiments). We also point out the possibility that the nonobservation of the 0νββ decay for some isotopes could be in agreement with a value of |mββ| in the sub-eV region. We thus suggest that it is important to have at least two different 0νββ-decay experiments for a given nucleus. We note that obtained results are sensitive to the accuracy of measured half-lives and to uncertainties in calculated nuclear matrix elements. © 2010 The American Physical Society.

Kohler R.,University of Southern Denmark | Ruth P.,University of Tubingen
Pflugers Archiv European Journal of Physiology | Year: 2010

K+ channels are important regulators of arterial tone by providing membrane hyperpolarization and thus counteracting the activity of voltage-gated Ca2+ channels in the smooth muscle and, thus, vasoconstriction. The endothelium and smooth muscle express a variety of different K+ channels, such as Ca2+-activated K + channels (KCa), voltage-gated (KV), two-pore-domain (K2P), and inward rectifying (KIR) and KATP channels. Their contributions to the numerous mechanisms of endothelium-dependent and smooth muscle-dependent relaxation are closely related to their electrophysiological properties, activation mechanisms, and to differential expressions pattern within the vascular wall. Here, we summarize the cardiovascular phenotypes in murine models of genetic K +-channel deficiency and focus, in particular, on defective vasoregulation in mice deficient of endothelial Ca2+-activated K + channels, IK (KCa3.1) and SK (KCa2.3), and smooth muscle Ca 2+-activated K+ channels, BK (KCa.1.1). Genetic deficiency of endothelial IK and SK severely impairs the endothelium-derived hyperpolarization-mediated type of arterial dilation. Moreover, SK deficiency impairs NO-mediated dilator responses, thus indicating subtype-specific actions in endothelial function. Loss of IK and/or SK channels is associated with sizeable higher blood pressure. In contrast, genetic deficiency of smooth BK channels enhances arterial blood pressure which is linked to mainly a loss of spontaneous transient outward currents in the smooth muscle cells as well as renal and adrenal gland functions (hyperaldosteronism). In conclusion, genetic deficiency of vascular K+ channels results in severe impairments of local and systemic blood pressure regulation. These alterations strengthen the perspective that vascular K+ channels are potential pharmacologic targets for improvement of vasodilator functions in cardiovascular pathologies. © 2010 Springer-Verlag.

Bankaitis V.A.,Lineberger Comprehensive Cancer Center | Mousley C.J.,Lineberger Comprehensive Cancer Center | Schaaf G.,University of Tubingen
Trends in Biochemical Sciences | Year: 2010

Lipid signaling pathways define central mechanisms for cellular regulation. Productive lipid signaling requires an orchestrated coupling between lipid metabolism, lipid organization and the action of protein machines that execute appropriate downstream reactions. Using membrane trafficking control as primary context, we explore the idea that the Sec14-protein superfamily defines a set of modules engineered for the sensing of specific aspects of lipid metabolism and subsequent transduction of 'sensing' information to a phosphoinositide-driven 'execution phase'. In this manner, the Sec14 superfamily connects diverse territories of the lipid metabolome with phosphoinositide signaling in a productive 'crosstalk' between these two systems. Mechanisms of crosstalk, by which non-enzymatic proteins integrate metabolic cues with the action of interfacial enzymes, represent unappreciated regulatory themes in lipid signaling. © 2009 Elsevier Ltd. All rights reserved.

Kalman O.,Hungarian Academy of Sciences | Kiss T.,Hungarian Academy of Sciences | Fortagh J.,University of Tubingen | Domokos P.,Hungarian Academy of Sciences
Nano Letters | Year: 2012

We evaluate the coupling of a Bose-Einstein condensate (BEC) of ultracold, paramagnetic atoms to the magnetic field of the current in a mechanically vibrating carbon nanotube within the frame of a full quantum theory. We find that the interaction is strong enough to sense quantum features of the nanowire current noise spectrum by means of hyperfine-state-selective atom counting. Such a nondestructive measurement of the electric current via its magnetic field corresponds to the classical galvanometer scheme, extended to the quantum regime of charge transport. The calculated high sensitivity of the interaction in the nanowire-BEC hybrid systems opens up the possibility of quantum control, which may be further extended to include other relevant degrees of freedom. © 2011 American Chemical Society.

Braeuning A.,University of Tubingen
Current Drug Metabolism | Year: 2012

The Wnt/β-catenin pathway plays an important role in liver homeostasis, as well as during prenatal liver development, liver regeneration, and hepatocarcinogenesis. The connection of hepatic β-catenin activation and expression of drug-metabolizing enzymes has been established in the past few years: on the whole, a generally positive-regulatory effect of β-catenin on the expression and inducibility of many enzymes involved in phase I and phase II of drug metabolism has been described by different groups. The mechanisms underlying these processes are still not fully understood. However, there is accumulating evidence for a complex interaction of β-catenin with different xenobiotic-sensing receptors, which act as transcription factors after ligand activation, for example the aryl hydrocarbon receptor or the constitutive androstane receptor. Among others, these crosstalk mechanisms might explain the manifold effects of β-catenin on hepatic drug metabolism. In this review, the current knowledge regarding the role of Wnt/β-catenin signaling in the regulation of hepatic expression of glutathione S-transferases is presented. In addition, the crosstalk of β-catenin signaling with nuclear receptors involved in the regulation of glutathione S-transferases will be discussed. © 2012 Bentham Science Publishers.

Adamopoulou E.,Hertie Institute for Clinical Brain Research | Naumann U.,University of Tubingen
OncoImmunology | Year: 2013

Natural killer (NK) cells are integral components of the antitumor immune response. The downregulation of ligands for NK-cell stimulatory receptors represents a strategy whereby glioblastoma cells can evade NK-cell attacks. Histone deacetylase inhibitors can stimulate the (re)expression of these ligands, driving cytotoxic responses against glioblastoma cells that efficiently inhibit tumor growth © 2013 Landes Bioscience.

Thorwarth D.,University of Tubingen
Nuclear Medicine Review | Year: 2012

Modern radiotherapy (RT) techniques allow a highly precise and flexible deposition of the radiation dose in the tumor. As a consequence, high conformal tumor doses can be reached while sparing critical organs at risk. Hence, it seems to be very beneficial to increase the dose in the tumor according to functional and molecular information assessed by combined PET/CT imaging. Such functional image guided dose escalation is called dose painting. Two different dose painting approaches have been described to date: dose painting by contours (DPC) and dose painting by numbers (DPBN). DPC consists of delineating an additional functional target volume on the PET/CT images and prescribing this volume homogeneously to a higher dose, whereas DPBN integrates the functional image information directly into the treatment planning process in order to shape the dose in a locally varying manner according to the PET information. Before dose painting strategies can be applied routinely in clinical practice, a number of factors that potentially affect the accuracy and effectiveness of dose painting, such as image acquisition and reconstruction protocols as well as image quantification will have to be investigated in the future. Nevertheless, integration of functional PET/CT imaging seems to be the cornerstone for advancing RT towards personalized patient-based treatment approaches. Copyright © 2012 Via Medica.

Shi S.,Huazhong University of Science and Technology | Klotz U.,Robert Bosch GmbH | Klotz U.,University of Tubingen
Clinical Pharmacokinetics | Year: 2012

In recent years, the issue of herbal medicine-drug interactions has generated significant concern. Such interactions can increase the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index (e.g. warfarin, ciclosporin and digoxin). The present article summarizes herbal medicine-drug interactions involving mainly inhibition or induction of cytochrome P450 enzymes andor drug transporters. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and the majority of the interactions may be difficult to predict. Potential pharmacodynamic andor pharmacokinetic interactions of commonly used herbal medicines (black cohosh, garlic, Ginkgo, goldenseal, kava, milk thistle, Panax ginseng, Panax quinquefolius, saw palmetto and St Johns wort) with conventional drugs are presented, and sometimes the results are contradictory. Clinical implications of herbal medicine-drug interactions depend on a variety of factors, such as the co-administered drugs, the patient characteristics, the origin of the herbal medicines, the composition of their constituents and the applied dosage regimens. To optimize the use of herbal medicines, further controlled studies are urgently needed to explore their potential for interactions with conventional drugs and to delineate the underlying mechanisms. © 2012 Adis Data Information BV. All rights reserved.

Altpeter E.K.,University of Tubingen
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society | Year: 2013

Leber hereditary optic neuropathy (LHON) is characterized by progressive loss of central vision leading to impaired reading ability. The aim of this study was to evaluate sensory adaptation and reading ability in LHON patients. This prospective pilot study included 12 male patients with a clinical diagnosis and a positive genetic analysis of LHON, who matched the inclusion criteria of a central scotoma on visual field testing and the use of magnifying aids to read. Examination included best-corrected visual acuity, magnification need, reading speed, and evaluation of fixation by corneal reflexes and by Rodenstock scanning laser ophthalmoscope (SLO). Central scotoma was assessed by conventional perimetry (Tübingen Automated Perimeter) and microperimetry (NIDEK MP1). Mean magnification need was 13.2 ± 7.3-fold (range: 2- to 25-fold). Mean reading speed was 53 ± 18 words per minute (WPM) (range: 24-85 WPM). With automated perimetry, all patients showed central scotomas with a mean radius of 13° ± 7° (range: 1°-30°) in the better eye. Microperimetry in all patients showed fenestrated central scotomas. Eccentric fixation with a preferred retinal locus (PRL) was detected with SLO examination and microperimetry correlated well in 11 of 12 patients. The SLO results showed no systematic pattern in the placement of the PRL; however, 7 of 12 patients (58%) placed their PRL in an unfavorable location left or below the fovea. In 8 of 12 patients, fixation was unstable. Between reading speed and central scotoma size, there was a statistically significant negative correlation (P = 0.021, r = -0.65). The percentage of unfavorable PRL locations was extremely high compared with other disorders with central scotomas. Unstable fixation and fenestrated central scotomas led to difficulties in reading. Early rehabilitation and, if necessary, eccentric viewing training should be considered in LHON patients.

Landerl K.,University of Tubingen | Moll K.,University of Salzburg
Journal of Child Psychology and Psychiatry and Allied Disciplines | Year: 2010

Background: In order to fully specify the profiles of risk and protective factors of developmental disorders, a better understanding of the conditions under which they co-occur is required. So far, empirical evidence on comorbidities of specific learning disorders in arithmetic, reading and spelling is scarce. Methods: Prevalence and gender ratios of specific learning disorders in arithmetic (AD), reading (RD), and spelling (SD) and their co-occurrence were assessed in a large (N = 2586) population-based sample of elementary school children and in a subsample of 293 children with at least one learning disorder (LD-sample). A questionnaire on familial transmission was given to a subsample of 256 parents of children with a learning disorder and 146 typically developing children. Results: The rates of deficits in arithmetic, reading, or spelling were four to five times higher in samples already experiencing marked problems in one academic domain compared to the full population. Thus, comorbidity of learning disorders was confirmed in a fairly standard school population. Rates of co-occurrence decreased for AD and RD, but not isolated SD when more stringent cutoff criteria were applied, suggesting that the comorbidity of arithmetic and spelling disorder may be more strongly biologically mediated than the comorbidity of arithmetic and reading disorder. We found a preponderance of girls with AD and boys with SD. These imbalanced gender ratios were especially marked for isolated problems, while for comorbid problems gender ratios were mostly balanced with the exception of deficits in arithmetic and reading (but not spelling) which were more typical for girls. The parental questionnaire provided evidence for disorder-specific familial transmission and co-segregation of arithmetic and literacy deficits. Conclusions: Comorbidities of learning disorders are not artificial. They are the result of a complex interplay between both general and disorder-specific aetiological factors. © 2009 Association for Child and Adolescent Mental Health.

The enantiomeric differentiation of the volatile chiral inhalation anesthetics enflurane, isoflurane, and desflurane by analytical and preparative gas chromatography on various modified cyclodextrins is described. Very large enantioseparation factors a are obtained on the chiral selector octakis(3-Obutanoyl- 2,6-di-O-pentyl)-?-cyclodextrin (Lipodex E). The gas-chromatographically observed enantioselectivities are corroborated byNMR-spectroscopy using Lipodex E as chiral solvating agent and by various sensor devices using Lipodex E as sensitive chiral coating layer. The assignment of the absolute configuration of desflurane is clarified.Methods are described for the determination of the enantiomeric distribution of chiral inhalation anesthetics during narcosis in clinical trials. The quantitation of enantiomers in a sample by the method of enantiomeric labeling is outlined. Reliable thermodynamic parameters of enantioselectivity are determined by using the retention-increment R0 approach for the enantiomeric differentiation of various chiral halocarbon selectands on diluted cyclodextrin selectors. © Springer-Verlag Berlin Heidelberg 2013.

Picard A.,University of Tubingen | Daniel I.,University Claude Bernard Lyon 1
Biophysical Chemistry | Year: 2013

Microbial life has been prevailing in the biosphere for the last 3.8 Ga at least. Throughout most of the Earth's history it has experienced a range of pressures; both dynamic pressure when the young Earth was heavily bombarded, and static pressure in subsurface environments that could have served as a refuge and where microbial life nowadays flourishes. In this review, we discuss the extent of high-pressure habitats in early and modern times and provide a short overview of microbial survival under dynamic pressures. We summarize the current knowledge about the impact of microbial activity on biogeochemical cycles under pressures characteristic of the deep subsurface. We evaluate the possibility that pressure can be a limiting parameter for life at depth. Finally, we discuss the open questions and knowledge gaps that exist in the field of high-pressure geomicrobiology. © 2013 Elsevier B.V.. All rights reserved.

Vagedes J.,University of Tubingen
Archives of disease in childhood. Fetal and neonatal edition | Year: 2013

Pulse oximeter saturation values are usually obtained by averaging over preceding measurements. This study investigates the dynamics between the averaging time and desaturation level, duration and extent. Prospective observational study of 15 preterm infants. Oxygen saturation was recorded for 168 h using a pulse oximeter. The raw red-to-infrared data were reprocessed using seven different averaging times to determine the number of desaturations below four thresholds and for seven different minimal desaturation durations. The total number of desaturations <80% was 339 with an averaging time of 16 s and 1958 with an averaging time of 3 s (minimal event duration >0 s). There was a significantly lower pulse oximeter saturation nadir with the shorter averaging time, while the maximum duration was significantly longer when using a 16 s averaging time. When using pulse oximeters, more attention should be given to averaging time and duration of desaturations.

The identification of in situ or reworked hearths in archaeological sediments is currently one of the main topics in archaeological micromorphology. In the case of shell-matrix sites (shell mounds and middens), the clast-supported matrix and high porosity can hamper the clear identification of combustion features. Previous experimental approaches were useful to identify in thin section the transformations induced by heating in mollusk shells, which are related to its mineralogy. Since different species of mollusks contain diverse mineralogy (aragonite, calcite, or both), it is expected that each species follows a specific thermal behavior, although similar general trends exist. In this short contribution, a set of valves of the mollusk Anomalocardia brasiliana (Gmelin 1791) (Bivalvia, Veneridae), the most important component of Brazilian shell mounds, was heated in a muffle furnace at temperatures from 200°C to 800°C. Thin sections were made and their description is presented for the identification of burnt shell of A. brasiliana. This information can help to infer the temperature of prehistoric fires and can assist in the identification of in situ versus reworked hearths in shell-matrix sites. © 2014 Wiley Periodicals, Inc.

Arquint C.,University of Basel | Sonnen K.F.,University of Basel | Stierhof Y.-D.,University of Tubingen | Nigg E.A.,University of Basel
Journal of Cell Science | Year: 2012

SummaryControl of centriole number is crucial for genome stability and ciliogenesis. Here, we characterize the role of human STIL, a protein that displays distant sequence similarity to the centriole duplication factors Ana2 in Drosophila and SAS-5 in Caenorhabditis elegans. Using RNA interference, we show that STIL is required for centriole duplication in human cells. Conversely, overexpression of STIL triggers the near-simultaneous formation of multiple daughter centrioles surrounding each mother, which is highly reminiscent of the phenotype produced by overexpression of the polo-like kinase PLK4 or the spindle assembly abnormal protein 6 homolog (SAS-6). We further show, by fluorescence and immunoelectron microscopy, that STIL is recruited to nascent daughter centrioles at the onset of centriole duplication and degraded, in an APC/CCdc20-Cdh1-dependent manner, upon passage through mitosis. We did not detect a stable complex between STIL and SAS-6, but the two proteins resemble each other with regard to both localization and cell cycle control of expression. Thus, STIL cooperates with SAS-6 and PLK4 in the control of centriole number and represents a key centriole duplication factor in human cells. © 2012.

Albert M.,University of Tubingen
Journal of Experimental Botany | Year: 2013

Plants are confronted with several biotic stresses such as microbial pathogens and other herbivores. To defend against such attackers, plants possess an array of pattern recognition receptors (PRRs) that sense the danger and consequently initiate a defence programme that prevents further damage and spreading of the pest. Characteristic pathogenic structures, so-called microbe-associated molecular patterns (MAMPs), serve as signals that allow the plant to sense invaders. Additionally, pathogens wound or damage the plant and the resulting release of damageassociated molecular patterns (DAMPs) serves as a warning signal. This review focuses on peptides that serve as triggers or amplifiers of plant defence and thus follow the definition of a MAMP or a DAMP. © The Author 2013. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved.

Nielsen M.E.,University of Tubingen | Thordal-Christensen H.,Copenhagen University
Trends in Plant Science | Year: 2013

Penetration resistance is a well-described plant defense process, in which SOLUBLE N-ETHYLMALEIMIDE-SENSITIVE-FACTOR ATTACHMENT RECEPTOR (SNARE) proteins have essential roles in membrane fusion processes. Strong focal accumulation of these proteins at the site of attack by powdery mildew fungi has been considered important for their function. However, recent insight indicates that transcytosis, leading to the formation of exosomes, has an important role in this defense and, furthermore, that strong accumulation of these SNARE proteins with the exosomes is biologically irrelevant. These findings alter the established function of SNAREs in penetration resistance; therefore, in this opinion, we propose that PEN1 and its SNARE partners function on an endosome in their control of penetration resistance. © 2013 Elsevier Ltd.

Nieder A.,University of Tubingen
Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology | Year: 2013

Humans share with nonhuman animals a quantification system for representing the number of items as nonverbal mental magnitudes. Over the past decade, the anatomical substrates and neuronal mechanisms of this quantification system have been unraveled down to the level of single neurons. Work with behaviorally trained nonhuman primates identified a parieto-frontal cortical network with individual neurons selectively tuned to the number of items. Such 'number neurons' can track items across space, time, and modality to encode numerosity in a most abstract, supramodal way. The physiological properties of these neurons can explain fundamental psychophysical phenomena during numerosity judgments. Functionally overlapping groups of parietal neurons represent not only numerable-discrete quantity (numerosity), but also innumerable-continuous quantity (extent) and relations between quantities (proportions), supporting the idea of a generalized magnitude system in the brain. These studies establish putative homologies between the monkey and human brain and demonstrate the suitability of nonhuman primates as model system to explore the neurobiological roots of the brain's nonverbal quantification system, which may constitute the evolutionary foundation of all further, more elaborate numerical skills in humans. © 2012 Springer-Verlag Berlin Heidelberg.

Zips D.,University of Tubingen | Baumann M.,TU Dresden
Seminars in Radiation Oncology | Year: 2013

Proton beam therapy offers potential dosimetric advantages coupled with complexities not currently encompassed in the photon radiotherapy experience. The practice is evolving alongside other developments in oncology, which include higher precision of photon radiotherapy, greater understanding of the biological effect of radiation and its potential modification, and the recognition of new molecular targets with a plethora of agents aimed at affecting biological function. For proton therapy to have an impact on clinical practice requires full examination in rigorous clinical trials comparing proton with best photon therapy. Only the results of present and future studies, showing equivalent, superior, or even potentially worse clinical results will shape their application. The desired goal is to develop personalized treatment strategies of fractionation appropriate for protons potentially combined with targeted agents. We describe the steps in health technology assessment and the potential design of preclinical and clinical trials to define the role of proton therapy in the future. © 2013 Elsevier Inc.

This paper investigates the enrolment trends and the critical factors that impinge on students' choice of physics as major field of study. The data were generated from primary and secondary sources. Primary data was acquired based on a semi-structured interview with 14 sophomore and 11 senior students and five instructors of the department of physics at Hawassa University, Ethiopia. In addition, data on allocation of students to various major fields as well as quantitative data on academic achievement were obtained from the university's registar office. The results indicate that the rate of enrolment in physics is the lowest and applicants who were assigned to the physics undergraduate programs were those whose mean score in Ethiopian National Higher Education Enterance Examination was the lowest compared to any other group. Further, the findings show unprecedented gender gap in enrollment and graduation rates. The explanations given for the low enrollment rate were inadequate pre-university preparation, weak mathematics background, lack of job opportunity outside the teaching profession, and poor teacher qualification and pedagogical content knowledge. Finally, this article forwards policy recommendations to bolster the alarmingly declining state of physics education in Ethiopia. © 2010 IJESE.

Heni M.,University of Tubingen
GMS Zeitschrift für medizinische Ausbildung | Year: 2012

Peer-assisted learning is widely used in medical education. However, little is known about an appropriate didactic preparation for peer tutors. We herein describe the development of a focused didactic training for skills lab tutors in Internal Medicine and report on a retrospective survey about the student tutors' acceptance and the perceived transferability of attended didactic training modules. The course consisted of five training modules: 1. 'How to present and explain effectively': the student tutors had to give a short presentation with subsequent video analysis and feedback in order to learn methods of effective presentation. 2. 'How to explain precisely': Precise explanation techniques were trained by exercises of exact description of geometric figures and group feedback. 3. 'How to explain on impulse': Spontaneous teaching presentations were simulated and feedback was given. 4. 'Peyton's 4 Step Approach': Peyton's Method for explanation of practical skills was introduced and trained by the participants. 5. 'How to deal with critical incidents': Possibilities to deal with critical teaching situations were worked out in group sessions. Twenty-three student tutors participated in the retrospective survey by filling out an electronic questionnaire, after at least 6 months of teaching experience. The exercise 'How to present and explain effectively' received the student tutors' highest rating for their improvement of didactic qualification and was seen to be most easily transferable into the skills lab environment. This module was rated as the most effective module by nearly half of the participants. It was followed by 'Peyton's 4 Step Approach' , though it was also seen to be the most delicate method in regard to its transfer into the skills lab owing to time concerns. However, it was considered to be highly effective. The other modules received lesser votes by the tutors as the most helpful exercise in improving their didactic qualification for skills lab teaching. We herein present a pilot concept for a focused didactic training of peer tutors and present results of a retrospective survey among our skills lab tutors about the distinct training modules. This report might help other faculties to design didactic courses for skills lab student tutors.

Munzer P.,University of Tubingen
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2016

OBJECTIVE—: Activation of platelets by subendothelial collagen results in an increase of cytosolic Ca concentration ([Ca]i) and is followed by platelet activation and thrombus formation that may lead to vascular occlusion. The present study determined the role of phosphoinositide-dependent protein kinase 1 (PDK1) in collagen-dependent platelet Ca signaling and ischemic stroke in vivo. APPROACH AND RESULTS—: Platelet activation with collagen receptor glycoprotein VI agonists collagen-related peptide or convulxin resulted in a significant increase in PDK1 activity independent of second-wave signaling. PDK1 deficiency was associated with reduced platelet phospholipase Cγ2–dependent inositol-1,4,5-trisphosphate production and intracellular [Ca]i in response to stimulation with collagen-related peptide or convulxin. The defective increase of [Ca]i resulted in a substantial defect in activation-dependent platelet secretion and aggregation on collagen-related peptide stimulation. Furthermore, Rac1 activation and spreading, adhesion to collagen, and thrombus formation under high arterial shear rates were significantly diminished in PDK1-deficient platelets. Mice with PDK1-deficient platelets were protected against arterial thrombotic occlusion after FeCl3-induced mesenteric arterioles injury and ischemic stroke in vivo. These mice had significantly reduced brain infarct volumes, with a significantly increased survival of 7 days after transient middle cerebral artery occlusion without increase of intracerebral hemorrhage. Tail bleeding time was prolonged in pdk1 mice, reflecting an important role of PDK1 in primary hemostasis. CONCLUSIONS—: PDK1 is required for Ca-dependent platelet activation on stimulation of collagen receptor glycoprotein VI, arterial thrombotic occlusion, and ischemic stroke in vivo. © 2016 American Heart Association, Inc.

Schmidt-Weigand F.,University of Kassel | Scheiter K.,University of Tubingen
Computers in Human Behavior | Year: 2011

In the reported experiment we investigated how spatial information conveyed in an expository text influenced multimedia learning. It was based on a 2 × 2-design with the degree of spatial information given in the text (high vs. low spatial text) and the presentation format (written text-only vs. written text + animation) as between-subjects factors. As dependent variables learning outcomes as well as self-reported cognitive load were assessed. The results revealed that there was a multimedia effect with regard to learning outcomes only for low spatial text, but not for high spatial text. Moreover, the cognitive load measures showed an overall multimedia effect irrespective of the degree of spatial information conveyed by the text (i.e., higher cognitive load ratings in the text-only conditions). These results can be explained as a special instance of the redundancy effect as well as a consequence of processing interference within visuo-spatial working memory. © 2010 Elsevier Ltd. All rights reserved.

Rodin V.,University of Tubingen
Journal of Physics: Conference Series | Year: 2012

The present status of calculations of the nuclear matrix elements for neutrinoless double beta decay is reviewed. Advantages and disadvantages of different nuclear structure models used for the calculations are discussed in detail.

Langenbacher M.,University of Tubingen
Strahlentherapie und Onkologie : Organ der Deutschen Röntgengesellschaft ... [et al] | Year: 2013

Tumor hypoxia is a major problem in radiation therapy of solid tumors because of the radiosensitizing effect of oxygen. Nitroimidazole-containing compounds are oxygen mimetics accumulating in hypoxic tumor areas. However, the broad use of 2-nitroimidazoles as a hypoxic radiosensitizer is limited by their partially low efficacy and/or high neurotoxicity. Here, we characterized the in vitro hypoxic cytotoxicity and hypoxic radiosensitizing efficacy of N,N,N-tris [2-(2-nitro-1H-imidazol-1-yl)ethyl]amine (PRC) in a hypoxia-sensitive lymphoma and a hypoxia-resistant glioblastoma cell line by colony formation assay and flow cytometry. PRC exerted high hypoxic cytotoxic and radiosensitizing action on both cell lines at almost absent toxicity under normoxic conditions. In particular, under hypoxia, but not normoxia, PRC targeted the mitochondria resulting in oxidative stress, G(2)/M cell cycle arrest, and triggering of the intrinsic apoptosis pathway. Our in vitro findings suggest that PRC might be a promising new 2-nitroimidazole for improving radiation therapy of hypoxic tumors in vivo.

Sprunck S.,University of Regensburg | Gross-Hardt R.,University of Tubingen
Sexual Plant Reproduction | Year: 2011

In flowering plants, the haploid gamete-forming generation comprises only a few cells and develops within the reproductive organs of the flower. The female gametophyte has become an attractive model system to study the genetic and molecular mechanisms involved in pattern formation and gamete specification. It originates from a single haploid spore through three free nuclear division cycles, giving rise to four different cell types. Research over recent years has allowed to catch a glimpse of the mechanisms that establish the distinct cell identities and suggests dynamic cell-cell communication to orchestrate not only development among the cells of the female gametophyte but also the interaction between male and female gametophytes. Additionally, cytological observations and mutant studies have highlighted the importance of nuclei migration- and positioning for patterning the female gametophyte. Here we review current knowledge on the mechanisms of cell specification in the female gametophyte, emphasizing the importance of positional cues for the establishment of distinct molecular profiles. © 2011 Springer-Verlag.

Symons S.,University of Tubingen
Journal of integrative bioinformatics | Year: 2010

Visualization is pivotal for gaining insight in systems biology data. As the size and complexity of datasets and supplemental information increases, an efficient, integrated framework for general and specialized views is necessary. MAYDAY is an application for analysis and visualization of general 'omics' data. It follows a trifold approach for data visualization, consisting of flexible data preprocessing, highly customizable data perspective plots for general purpose visualization and systems based plots. Here, we introduce two new systems biology visualization tools for MAYDAY. Efficiently implemented genomic viewers allow the display of variables associated with genomic locations. Multiple variables can be viewed using our new track-based ChromeTracks tool. A functional perspective is provided by visualizing metabolic pathways either in KEGG or BioPax format. Multiple options of displaying pathway components are available, including Systems Biology Graphical Notation (SBGN) glyphs. Furthermore, pathways can be viewed together with gene expression data either as heatmaps or profiles. We apply our tools to two 'omics' datasets of Pseudomonas aeruginosa. The general analysis and visualization tools of MAYDAY as well as our ChromeTracks viewer are applied to a transcriptome dataset. We furthermore integrate this dataset with a metabolome dataset and compare the activity of amino acid degradation pathways between these two datasets, by visually enhancing the pathway diagrams produced by MAYDAY.

Emanuel Gil-Av (Zimkin) was born in 1916 and passed away in 1996. The introduction of chemical selectivity into the chromatographic separation process constitutes his main scientific contribution. This approach culminated in the first enantiomeric separation of racemic amino acids by gas chromatography on an optically active chiral stationary phase in 1966, together with Binyamin Feibush and Rosita Charles-Sigler. Thus the year 2016 marks an important date to remember and to appreciate the invaluable achievements of Gil-Av in the realm of chirality carried out at the Weizmann Institute of Science, Israel. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ilg W.,University of Tubingen | Timmann D.,University of Duisburg - Essen
Movement Disorders | Year: 2013

It is well known that the cerebellum is important for movement control and plays a critical role in balance and locomotion. As such, one of the most characteristic and sensitive signs of cerebellar damage is gait ataxia. However, characterizing ataxic gait is no easy task, because gait patterns are highly variable. This variability seems to result from the interaction of different factors, namely, (1) the primary motor deficits in balance control and multi-joint coordination and oculomotor dysfunction, (2) the safety strategies used, and (3) inaccurate adjustments in patients with loss of balance. In this report, we review different approaches to analyzing ataxic gait and studies to identify and quantify the different factors contributing to this movement disorder. We also discuss the influence of the cerebellum in adaptive locomotor control, the interaction between cognitive load and gait in dual-task paradigms, and the recent advances in rehabilitation of gait and posture for patients with cerebellar degeneration. In the second part, we discuss open questions concerning cerebellar mechanisms in multi-joint coordination during different walking conditions. Furthermore, we point out potential future directions in motor rehabilitation, with the objective of identifying predictors of rehabilitation outcome and the development of individualized training programs that potentially involve rehabilitation technology. © 2013 Movement Disorder Society.

Martin S.,TU Braunschweig | Bange J.,University of Tubingen
Boundary-Layer Meteorology | Year: 2014

Crawford et al. (Boundary-Layer Meteorol 66:237-245, 1993) showed that the time average is inappropriate for airborne eddy-covariance flux calculations. The aircraft's ground speed through a turbulent field is not constant. One reason can be a correlation with vertical air motion, so that some types of structures are sampled more densely than others. To avoid this, the time-sampled data are adjusted for the varying ground speed so that the modified estimates are equivalent to spatially-sampled data. A comparison of sensible heat-flux calculations using temporal and spatial averaging methods is presented and discussed. Data of the airborne measurement systems M2AV, Helipod and Dornier 128-6 are used for the analysis. These systems vary in size, weight and aerodynamic characteristics, since theM2AV is a small unmanned aerial vehicle (UAV), the Helipod a helicopter-borne turbulence probe and the Dornier 128-6 a manned research aircraft. The systematic bias anticipated in covariance computations due to speed variations was neither found when averaging over Dornier, Helipod nor UAV flight legs. However, the random differences between spatial and temporal averaging fluxes were found to be up to 30 % on the individual flight legs. © 2013 Springer Science+Business Media Dordrecht.

Reinhardt K.,University of Tubingen | Reinhardt K.,University of Sheffield | Dowling D.K.,Monash University | Morrow E.H.,University of Sussex
Science | Year: 2013

Mitochondrial replacement therapy might bear health risks, especially for males.

Goetz M.,University of Tubingen
Gastrointestinal Endoscopy Clinics of North America | Year: 2013

Confocal laser endomicroscopy (CLE) allows microscopic imaging of the gastric mucosa in real time during endoscopy. Gastroenterologists are able to evaluate gastric pathologies in real time, which is used to target fewer biopsies to regions of interest by providing multiple " optical" biopsies, and guide endoscopic interventions. CLE provides a powerful tool for translational studies to unravel the pathophysiology of diseases in vivo virtually free of artifacts. Molecular imaging may help to detect suspicious lesions and to predict response to targeted therapy. This review provides an overview of current applications of endomicroscopy of the stomach in clinical and translational science. © 2013 Elsevier Inc.

Lehtonen J.,Australian National University | Schmidt D.J.,Griffith University | Heubel K.,University of Tubingen | Kokko H.,Australian National University
Trends in Ecology and Evolution | Year: 2013

Sexual parasites offer unique insights into asexual and sexual reproduction. They mate with a 'host' whose genetic contribution is discarded either immediately (in androgenesis or gynogenesis) or after a delay of one generation (in hybridogenesis). The discarded genome can be maternal or paternal, implying that not only females but also males can reproduce asexually. The resulting lineages are often older than ecological or evolutionary theory predicts. Sexual parasites have links to a diverse set of concepts: selfish genetic elements, degradation of clonal genomes, evolution of sex, mate-choice theory, and host-parasite dynamics. We discuss the different sexually parasitic systems in both hermaphrodites and gonochoristic organisms, emphasizing their similarities and differences in ecological and evolutionary settings. © 2013 Elsevier Ltd.

Galan J.E.,Yale University | Lara-Tejero M.,Yale University | Marlovits T.C.,German Electron Synchrotron | Marlovits T.C.,Austrian Academy of Sciences | And 2 more authors.
Annual Review of Microbiology | Year: 2014

One of the most exciting developments in the field of bacterial pathogenesis in recent years is the discovery that many pathogens utilize complex nanomachines to deliver bacterially encoded effector proteins into target eukaryotic cells. These effector proteins modulate a variety of cellular functions for the pathogen's benefit. One of these protein-delivery machines is the type III secretion system (T3SS). T3SSs are widespread in nature and are encoded not only by bacteria pathogenic to vertebrates or plants but also by bacteria that are symbiotic to plants or insects. A central component of T3SSs is the needle complex, a supramolecular structure that mediates the passage of the secreted proteins across the bacterial envelope. Working in conjunction with several cytoplasmic components, the needle complex engages specific substrates in sequential order, moves them across the bacterial envelope, and ultimately delivers them into eukaryotic cells. The central role of T3SSs in pathogenesis makes them great targets for novel antimicrobial strategies. Copyright © 2014 by Annual Reviews. All rights reserved.

Cirpka O.A.,University of Tubingen
Water Resources Research | Year: 2010

Biodegradation of continuously emitted compounds that need a dissolved reaction partner, which is not jointly introduced with the contaminant into the subsurface, is mainly controlled by transverse dispersive mixing. Previous analytical approaches of evaluating mixing-controlled bioreactive transport in steady state have been based on the assumption that the bulk aqueous-phase concentration of the reactants is directly available to the specific biomass catalyzing the reaction. These models predict a very narrow stripe of active biomass with high specific biomass concentration. Experimental studies have indicated that such behavior may be unrealistic, particularly for anaerobic biodegradation. I extend the previous analysis to include kinetic solute uptake by the biomass, expressed as a first-order mass-transfer process coupled to dual Monod kinetics in the bio-available domain. The approach is based on the evaluation of conservative components undergoing advective-dispersive transport, the solution of a quadratic speciation problem within the immobile bio domain, and iterative simulation of linear transport of a single reactive constituent in steady state. Convergence is typically achieved within less than ten iterations. The comparison with simulations assuming instantaneous solute uptake by the biomass indicate that mass-transfer kinetics may explain larger overlap of reactive constituents and a wider spatial distribution of specific biomass observed in experiments. Depending on the rate coefficient of mass transfer, the overall transformation of the contaminant may be significantly reduced or only slightly shifted to a region farther downstream. © 2010 by the American Geophysical Union.

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.

Morasch B.,Ecole Polytechnique Federale de Lausanne | Morasch B.,University of Tubingen
Environmental Pollution | Year: 2013

Karst systems represent important yet vulnerable drinking water resources. A wide spectrum of pollutants may be released into karst groundwater from agriculture, livestock farming, private households, and industry. This work provides an overview on the occurrence and dynamics of micropollutants in a karst system of the Swiss Jura. Ten months of intensive monitoring for micropollutants confirmed that the swallow hole draining an agricultural plain was the main entry path for pesticides into the karst system and the two connected springs. Elevated fungicide concentrations in winter and occasional quantification of pharmaceuticals suggested wood- or façade treatment and domestic sewer as additional sources of contamination. A continuous atrazine signal in the low ng/L range might affect the autochthonous endokarst microbial community and represents a potential risk for the human population through karst groundwater. © 2012 Elsevier Ltd. All rights reserved.

The aetiology of primary biliary cirrhosis (PBC) remains unknown. Infectious and non-infectious noxious insults in combination with tissue-specific factors may precipitate PBC. Activation of innate immune response because of impending danger signals seems to be a key event in early PBC, as evidenced by granuloma formation, eosinophilic reaction and IgM elevation. Aberrant mitophagy in 'stressed' biliary epithelia cells may initiate the immune response against mitochondrial antigens. Antimitochondrial autoantibodies recognize evolutionarily conserved molecules. The question arises, whether they are pathogenic or rather an expression of beneficial autoimmunity. The generally stable course of PBC suggests that stimulatory and inhibitory autoimmune reactions govern the inflammatory biliary process. Tissue repair and defense are the heart of innate immunity. But continuous exposure of exogenous stimuli may precipitate functional antireceptor autoantibodies that are no more protective but rather harmful. Mitophagy, apoptosis and bile duct proliferation define the inflammatory response within bile ducts. Autoantigens may be clustered in different blebs on the surface of apoptotic cells targeting a variety of membrane and non-membrane-associated antigens. Thus, the autoantibody response in PBC may target, for instance, the pro- and anti-apoptotic proteins of the Bcl-2 family or receptors of the adrenergic or cholinergic system, hereby interfering with the programme of apoptosis and the proliferation of biliary epithelial cells. Consideration of there being functional autoantibodies into the pathogenesis of PBC may help to improve our understanding of the aetiopathogenesis of PBC. © 2011 John Wiley & Sons A/S.

Schaeffel F.,University of Tubingen
Klinische Monatsblatter fur Augenheilkunde | Year: 2011

This review summarises some recent aspects of myopia research. The following conclusions have been drawn. As long as myopia progression is visually controlled, at least three different interventions are possible: (i) spectacles/contact lenses which correct only the centre of the visual field and leave the periphery somewhat myopic, (ii) outdoor activity or equivalent temporary increase in illuminance, (iii) pharmacological intervention of retinal growth signals that are transmitted to the underlying sclera. Options (i) and (ii) can be used without risks although there is still room for improvement of the variables. Option (iii) has re-entered a new phase of orientation with new searches for candidate targets after previous testing with muskarinic antagonists (pirenzepine) in children did not enter phase 3 level. If myopia is outside the range over which it is visually controlled by emmetropisation (in the case of high and pathological myopias), in principle the possibility exists to improve the mechanical stability of the sclera pharmacologically. However, there is still a need for more research. Up to now, the mechanical weakness of the sclera in highly mopyic eyes is surgically stabilised by scleral buckling. However, these procedures have found limited acceptance since the effects were not very reliable. In 40 50 % of the cases of high myopia, degenerative processes are found in the retina which can be seen as consequence of the mechanical tension in the fundus, but may also be indepedent of this factor (no significant correlation with axial length!). In part they can be slowed down by intravitreal anti-VEGF therapy. A long-term study from Denmark has shown that most patients with myopia of between 6 9 dpt during puberty reach retirement age without disabling visual loss. ©Georg Thieme Verlag KG Stuttgart.

Lang F.,University of Tubingen | Hoffmann E.K.,Copenhagen University
Comprehensive Physiology | Year: 2012

Cell shrinkage is a hallmark and contributes to signaling of apoptosis. Apoptotic cell shrinkage requires ion transport across the cell membrane involving K+ channels, Cl- or anion channels, Na+/H+ exchange, Na+,K+,Cl- cotransport, and Na+/K+ATPase. Activation of K+ channels fosters K+ exit with decrease of cytosolic K+ concentration, activation of anion channels triggers exit of Cl-, organic osmolytes, and HCO3. Cellular loss of K+ and organic osmolytes as well as cytosolic acidification favor apoptosis. Ca2+ entry through Ca2+-permeable cation channels may result in apoptosis by affecting mitochondrial integrity, stimulating proteinases, inducing cell shrinkage due to activation of Ca2+-sensitive K+ channels, and triggering cell-membrane scrambling. Signaling involved in the modification of cell-volume regulatory ion transport during apoptosis include mitogen-activated kinases p38, JNK, ERK1/2, MEKK1, MKK4, the small G proteins Cdc42, and/or Rac and the transcription factor p53. Osmosensing involves integrin receptors, focal adhesion kinases, and tyrosine kinase receptors. Hyperosmotic shock leads to vesicular acidification followed by activation of acid sphingomyelinase, ceramide formation, release of reactive oxygen species, activation of the tyrosine kinase Yes with subsequent stimulation of CD95 trafficking to the cell membrane. Apoptosis is counteracted by mechanisms involved in regulatory volume increase (RVI), by organic osmolytes, by focal adhesion kinase, and by heat-shock proteins. Clearly, our knowledge on the interplay between cell-volume regulatory mechanisms and suicidal cell death is still far from complete and substantial additional experimental effort is needed to elucidate the role of cell-volume regulatory mechanisms in suicidal cell death. © 2012 American Physiological Society.

Huber M.,University of Tubingen
Cryptography and Communications | Year: 2010

We present several generalizations of results for splitting authentication codes by studying the aspect of multi-fold security. As the two primary results, we prove a combinatorial lower bound on the number of encoding rules and a combinatorial characterization of optimal splitting authentication codes that are multi-fold secure against spoofing attacks. The characterization is based on a new type of combinatorial designs, which we introduce and for which basic necessary conditions are given regarding their existence. © 2010 Springer Science + Business Media, LLC.

Eich T.,University of Tubingen
Culture, Health and Sexuality | Year: 2010

In the Sunni Arab world, hymen repair has become a subject of considerable controversy due to a public statement of Egypt's Mufti Guma(a in 2007. This paper analyses Guma(a's position and the ensuing public debate about it as a means to study the larger conceptions of virginity and the hymen in Middle Eastern societies. In line with critical feminist studies it is shown that supporters as well as critics of the operation rely heavily on patriarchal arguments, views and rhetoric. Both share the societal vision that sexuality can only be lived out licitly in the framework of marriage and both agree that this ideal is in crisis. Where the two sides disagree is over the way in which this ideal should be protected, which derives from their conceptualisation of creation in general and female nature in particular. As a result, debate about hymen repair is not only not transforming social structures but is perpetuating them. © 2010 Taylor & Francis.

Heide L.,University of Tubingen
International Journal of Medical Microbiology | Year: 2014

The aminocoumarins novobiocin, clorobiocin and coumermycin A1 are structurally related antibiotics produced by different Streptomyces strains. They are potent inhibitors of bacterial gyrase. Their binding sites and their mode of action differ from those of fluoroquinolones such as ciprofloxacin. Novobiocin has been introduced into clinical use against Staphylococcus aureus infections, and S. aureus gyrase is particularly sensitive to inhibition by aminocoumarins, while topoisomerase IV is much less sensitive. Modern genetic techniques have allowed the engineering of the producer strains, resulting in a diverse range of new aminocoumarins, including compounds which are more active than the natural antibiotics as well as a compound which is actively imported across the cell envelope of Gram-negative bacteria. A further group of aminocoumarins are the simocyclinones which bind simultaneously to two different sites of gyrase and show a completely new mode of inhibition. Both the simocyclinones and the "classical" aminocoumarins strongly inhibit the fluoroquinolone-induced activation of RecA and thereby the SOS response in S. aureus. Therefore, a combination of aminocoumarins and fluoroquinolones strongly reduced the risk of resistance development and may offer new prospects in anti-infective therapy. © 2013 Elsevier GmbH.

Kjaer S.K.,Danish Cancer Society | Kjaer S.K.,Copenhagen University | Frederiksen K.,Danish Cancer Society | Munk C.,Danish Cancer Society | Iftner T.,University of Tubingen
Journal of the National Cancer Institute | Year: 2010

Background Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type-specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types. Methods A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time. Results For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%). Conclusion HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA-negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary. © The Author 2010. Published by Oxford University Press.

Muller-Dahlhaus F.,University of Tubingen | Vlachos A.,Goethe University Frankfurt
Frontiers in Molecular Neuroscience | Year: 2013

Despite numerous clinical studies, which have investigated the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) in various brain diseases, our knowledge of the cellular and molecular mechanisms underlying rTMS-based therapies remains limited. Thus, a deeper understanding of rTMS-induced neural plasticity is required to optimize current treatment protocols. Studies in small animals or appropriate in vitro preparations (including models of brain diseases) provide highly useful experimental approaches in this context. State-of-the-art electrophysiological and live-cell imaging techniques that are well established in basic neuroscience can help answering some of the major questions in the field, such as (i) which neural structures are activated during TMS, (ii) how does rTMS induce Hebbian plasticity, and (iii) are other forms of plasticity (e.g., metaplasticity, structural plasticity) induced by rTMS? We argue that data gained from these studies will support the development of more effective and specific applications of rTMS in clinical practice. © 2013 Müller-DahlhausandVlachos.

Huber S.M.,University of Tubingen
Microbes and Infection | Year: 2012

Human erythrocytes are endowed with ATP release pathways and metabotropic and ionotropic purinoceptors. This review summarizes the pivotal function of purinergic signaling in erythrocyte control of vascular tone, in hemolytic septicemia, and in malaria. In malaria, the intraerythrocytic parasite exploits the purinergic signaling of its host to adapt the erythrocyte to its requirements. © 2012 Institut Pasteur.

Scrivano L.,Ludwig Maximilians University of Munich | Sinzger C.,University of Tubingen | Nitschko H.,Ludwig Maximilians University of Munich | Koszinowski U.H.,Ludwig Maximilians University of Munich | Adler B.,Ludwig Maximilians University of Munich
PLoS Pathogens | Year: 2011

Human cytomegalovirus (HCMV) can infect many different cell types in vivo. Two gH/gL complexes are used for entry into cells. gH/gL/pUL(128,130,131A) shows no selectivity for its host cell, whereas formation of a gH/gL/gO complex only restricts the tropism mainly to fibroblasts. Here, we describe that depending on the cell type in which virus replication takes place, virus carrying the gH/gL/pUL(128,130,131A) complex is either released or retained cell-associated. We observed that virus spread in fibroblast cultures was predominantly supernatant-driven, whereas spread in endothelial cell (EC) cultures was predominantly focal. This was due to properties of virus released from fibroblasts and EC. Fibroblasts released virus which could infect both fibroblasts and EC. In contrast, EC released virus which readily infected fibroblasts, but was barely able to infect EC. The EC infection capacities of virus released from fibroblasts or EC correlated with respectively high or low amounts of gH/gL/pUL(128,130,131A) in virus particles. Moreover, we found that focal spread in EC cultures could be attributed to EC-tropic virus tightly associated with EC and not released into the supernatant. Preincubation of fibroblast-derived virus progeny with EC or beads coated with pUL131A-specific antibodies depleted the fraction that could infect EC, and left a fraction that could predominantly infect fibroblasts. These data strongly suggest that HCMV progeny is composed of distinct virus populations. EC specifically retain the EC-tropic population, whereas fibroblasts release EC-tropic and non EC-tropic virus. Our findings offer completely new views on how HCMV spread may be controlled by its host cells. © 2011 Scrivano et al.

Beisner J.,University of Tubingen
Gut microbes | Year: 2011

Defects in the intestinal barrier play a central role in disease pathogenesis. Recently we have demonstrated that children with ileal Crohn's disease show a reduced expression of small intestinal HD-5 at the age of onset suggesting that a compromised mucosal barrier function might be a key factor in the early disease pathogenesis. We also identified a disturbance of the Wnt signaling transcription factor TCF-4 as a major mechanism for this deficiency in children which might result in a compromised innate immune function of small intestinal Paneth cells via defensin secretion. Here we provide a summary on our recent findings and discuss the data in more detail especially focusing on the role of Paneth cell differentiation and function in the pathogenesis of pediatric ileal Crohn's disease. © 2011 Landes Bioscience

Schwarz C.,University of Tubingen
Cerebellum | Year: 2010

How does the cerebellum participate in neocortical rhythms? Neocortical signals destined for the cerebellum are integrated in the pontine nuclei (PN) with cerebellar output signals via a direct, reciprocal feedback loop with the cerebellar nuclei (CN). The present study investigated the fate of two spontaneously occurring rhythms in rat neocortex under ketamine anesthesia-slow wave activity at around 1 Hz and gamma oscillations-within this pontonuclear feedback loop. Coordinated oscillatory neuronal activity was studied using simultaneous multineuron recordings in primary motor cortex (M1), PN, and lateral CN. It was revealed that slow burst firing-known in neocortex as "up and down states"-is readily conveyed within the pontonuclear feedback loop and thus engages the entire cerebropontocerebellothalamic loop. In contrast, gamma band synchronous oscillations reached only the PN under the present experimental conditions. Surprisingly, many CN single units were actually found to oscillate in the gamma range, but they completely failed to synchronize with other units in either CN or PN. These results show firstly that slow concerted activity can readily engage the entire cerebrocerebellar loop. Secondly, they raise the possibility that fast gamma oscillations may be incompatible with cerebellar processing and get blocked out. Future studies in behaving animals are needed to answer the question whether signals coded in gamma band frequency are converted to another carrier code using the feedback control exerted by the pontonuclear loop. © 2009 Springer Science+Business Media, LLC.

Ackermann H.,University of Tubingen | Riecker A.,University of Ulm
Brain Structure and Function | Year: 2010

Skilled spoken language production requires fast and accurate coordination of up to 100 muscles. A long-standing concept-tracing ultimately back to Paul Broca-assumes posterior parts of the inferior frontal gyrus to support the orchestration of the respective movement sequences prior to innervation of the vocal tract. At variance with this tradition, the insula has more recently been declared the relevant "region for coordinating speech articulation", based upon clinico-neuroradiological correlation studies. However, these findings have been criticized on methodological grounds. A survey of the clinical literature (cerebrovascular disorders, brain tumours, stimulation mapping) yields a still inconclusive picture. By contrast, functional imaging studies report more consistently hemodynamic insular responses in association with motor aspects of spoken language. Most noteworthy, a relatively small area at the junction of insular and opercular cortex was found sensitive to the phonetic-linguistic structure of verbal utterances, a strong argument for its engagement in articulatory control processes. Nevertheless, intrasylvian hemodynamic activation does not appear restricted to articulatory processes and might also be engaged in the adjustment of the autonomic system to ventilatory needs during speech production: Whereas the posterior insula could be involved in the cortical representation of respiration-related metabolic (interoceptive) states, the more rostral components, acting upon autonomic functions, might serve as a corollary pathway to "voluntary control of breathing" bound to corticospinal and -bulbar fiber tracts. For example, the insula could participate in the implementation of task-specific autonomic settings such as the maintenance of a state of relative hyperventilation during speech production. © 2010 Springer-Verlag.

Surovtsev Y.S.,Joint Institute for Nuclear Research | Bydovsky P.,Nuclear Physics Institute of Czech Republic | Lyubovitskij V.E.,University of Tubingen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2012

The experimental data on the processes ππ→ππ, KK̄, ηη, ηη ′ in the IGJPC=0 +0 ++ channel have been jointly analyzed to study the status and nature of the f 0. The method of analysis is based on analyticity and unitarity and uses an uniformization procedure. Some spectroscopic implications from results of the analysis are discussed. © 2012 American Physical Society.

Kelemen E.,New York University | Kelemen E.,University of Tubingen | Fenton A.A.,New York University
PLoS Biology | Year: 2013

Neurophysiological studies focus on memory retrieval as a reproduction of what was experienced and have established that neural discharge is replayed to express memory. However, cognitive psychology has established that recollection is not a verbatim replay of stored information. Recollection is constructive, the product of memory retrieval cues, the information stored in memory, and the subject's state of mind. We discovered key features of constructive recollection embedded in the rat CA1 ensemble discharge during an active avoidance task. Rats learned two task variants, one with the arena stable, the other with it rotating; each variant defined a distinct behavioral episode. During the rotating episode, the ensemble discharge of CA1 principal neurons was dynamically organized to concurrently represent space in two distinct codes. The code for spatial reference frame switched rapidly between representing the rat's current location in either the stationary spatial frame of the room or the rotating frame of the arena. The code for task variant switched less frequently between a representation of the current rotating episode and the stable episode from the rat's past. The characteristics and interplay of these two hippocampal codes revealed three key properties of constructive recollection. (1) Although the ensemble representations of the stable and rotating episodes were distinct, ensemble discharge during rotation occasionally resembled the stable condition, demonstrating cross-episode retrieval of the representation of the remote, stable episode. (2) This cross-episode retrieval at the level of the code for task variant was more likely when the rotating arena was about to match its orientation in the stable episode. (3) The likelihood of cross-episode retrieval was influenced by preretrieval information that was signaled at the level of the code for spatial reference frame. Thus key features of episodic recollection manifest in rat hippocampal representations of space. © 2013 Kelemen, Fenton.

Future hazards which may result from genetically engineered plants can currently only be anticipated. Therefore, the handling of the potential risks is becoming a crucial political and legal question. The following article describes the differing national regulatory approaches in Europe: an economic, a scientific, and a sociopolitical approach pre-existed the European Unions deliberate release Directive, which itself follows a primarily science-based approach. The latter is based on objective technological assessments of individual cases. At the same time, however, the Directive contains elements of a sociocultural approach, which is open to value-based judgments and thus, necessarily takes a subjective, general assessment of the use of genetically modified organisms. As a result, the European law of Agricultural Genetic Engineering provides two paths of risk regulation in parallel. © 2013 Taylor and Francis Group, LLC.

Gallwitz B.,University of Tubingen
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2016

Purpose of review Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are gastrointestinal peptides that play an important role as incretin hormones in the regulation of plasma glucose and insulin secretion. GLP-1-based therapies have therefore been implemented as treatment for type 2 diabetes (T2D). The purpose of this review is to summarize novel treatment options for T2D with GLP-1-based therapies. In addition, both peptides have relevant extrapancreatic effects that have been further characterized recently and are summarized in this review. Recent findings Novel findings regarding changes in GLP-1 secretion after bariatric surgery are highlighted, wherein GLP-1 plays a role in promoting body weight loss and diabetes remission. For T2D therapy, novel options with long-acting GLP-1 analogs are summarized that show a good efficacy and safety profile, also in combination with insulin as well as for obesity treatment. As GIP is not suitable for T2D therapy, extrapancreatic effects of GIP, mainly on bone metabolism that have been characterized recently, are described. These show that the activated GIP receptor is important to allow optimal bone mass and structure. Summary This review summarizes new findings on the physiology and pathophysiology of GLP-1 and GIP and novel therapeutic aspects. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Skomski D.,Indiana University Bloomington | Abb S.,Indiana University Bloomington | Abb S.,University of Tubingen | Tait S.L.,Indiana University Bloomington
Journal of the American Chemical Society | Year: 2012

Ionic bonding in supramolecular surface networks is a promising strategy to self-assemble nanostructures from organic building blocks with atomic precision. However, sufficient thermal stability of such systems has not been achieved at metal surfaces, likely due to partial screening of the ionic interactions. We demonstrate excellent stability of a self-assembled ionic network on a metal surface at elevated temperatures. The structure is characterized directly by atomic resolution scanning tunneling microscopy (STM) experiments conducted at 165 °C showing intact domains. This robust nanometer-scale structure is achieved by the on-surface reaction of a simple and inexpensive compound, sodium chloride, with a model system for carboxylate interactions, terephthalic acid (TPA). Rather than distinct layers of TPA and NaCl, angle resolved X-ray photoelectron spectroscopy experiments indicate a replacement reaction on the Cu(100) surface to form Na-carboxylate ionic bonds. Chemical shifts in core level electron states confirm a direct interaction and a +1 charge state of the Na. High-temperature STM imaging shows virtually no fluctuation of Na-TPA island boundaries, revealing a level of thermal stability that has not been previously achieved in noncovalent organic-based nanostructures at surfaces. Comparable strength of intermolecular ionic bonds and intramolecular covalent bonds has been achieved in this surface system. The formation of these highly ordered structures and their excellent thermal stability is dependent on the interplay of adsorbate-substrate and ionic interactions and opens new possibilities for ionic self-assemblies at surfaces with specific chemical function. Robust ionic surface structures have potential uses in technologies requiring high thermal stability and precise ordering through self-assembly. © 2012 American Chemical Society.

Toulany M.,University of Tubingen
Nuklearmedizin. Nuclear medicine | Year: 2010

Accumulated evidence indicates that activation of erbB family of receptors, when mutated or over-expressed, mediates chemo- and radiotherapy resistance. In this context signaling pathways down-stream of epidermal growth factor receptor (EGFR), when abnormally activated, invoke cell survival mechanisms, which leads to resistance against radiation. In several reports it has been demonstrated that molecular targeting of EGFR signaling enhances the cytotoxic effects of radiotherapy. The radiosensitizing effects of EGFR antagonists correlate with a suppression of the ability of tumor cells to repair radiation-induced DNA double strand breaks (DNA-DSBs) through non-homologous end-joining repair pathway (NHEJ). The purpose of this review is to highlight the function of EGFR and erbB2 receptors on signaling pathways, i. e. PI3K/Akt activated by ionizing radiation (IR) and involved in repair of DNA-DSB which can explain the radiosensitizing effects of related antagonists. Advances in understanding the mechanism of erbB-signaling in regulating DNA-DSB repair will promote translational approaches to test new strategies for clinically applicable molecular targeting.

Ackermann H.,University of Tubingen
Brain structure & function | Year: 2010

Skilled spoken language production requires fast and accurate coordination of up to 100 muscles. A long-standing concept--tracing ultimately back to Paul Broca--assumes posterior parts of the inferior frontal gyrus to support the orchestration of the respective movement sequences prior to innervation of the vocal tract. At variance with this tradition, the insula has more recently been declared the relevant "region for coordinating speech articulation", based upon clinico-neuroradiological correlation studies. However, these findings have been criticized on methodological grounds. A survey of the clinical literature (cerebrovascular disorders, brain tumours, stimulation mapping) yields a still inconclusive picture. By contrast, functional imaging studies report more consistently hemodynamic insular responses in association with motor aspects of spoken language. Most noteworthy, a relatively small area at the junction of insular and opercular cortex was found sensitive to the phonetic-linguistic structure of verbal utterances, a strong argument for its engagement in articulatory control processes. Nevertheless, intrasylvian hemodynamic activation does not appear restricted to articulatory processes and might also be engaged in the adjustment of the autonomic system to ventilatory needs during speech production: Whereas the posterior insula could be involved in the cortical representation of respiration-related metabolic (interoceptive) states, the more rostral components, acting upon autonomic functions, might serve as a corollary pathway to "voluntary control of breathing" bound to corticospinal and -bulbar fiber tracts. For example, the insula could participate in the implementation of task-specific autonomic settings such as the maintenance of a state of relative hyperventilation during speech production.

Simon M.,University of Tubingen | Buchner A.,Heinrich Heine University Dusseldorf
International Journal of Psychophysiology | Year: 2012

The intention of this paper is to describe neurophysiological correlates of driver distraction with highly robust parameters in the EEG (i.e. alpha spindles). In a simulated driving task with two different secondary tasks (i.e. visuomotor, auditory), N= 28 participants had to perform full stop brakes reacting to appearing stop signs and red traffic lights. Alpha spindle rate was significantly higher during an auditory secondary task and significantly lower during a visuomotor secondary task as compared to driving only. Alpha spindle duration was significantly shortened during a visuomotor secondary task. The results are consistent with the assumption that alpha spindles indicate active inhibition of visual information processing. Effects on the alpha spindles while performing secondary tasks on top of the driving task indicate attentional shift according to the task modality. As compared to alpha band power, both the measures of alpha spindle rate and alpha spindle duration were less vulnerable to artifacts and the effect sizes were larger, allowing for a more accurate description of the current driver state. © 2011 Elsevier B.V.

Schittek B.,University of Tubingen
Current Problems in Dermatology | Year: 2011

Keratinocytes represent the major cell population in the epithelial skin barrier and actively participate in innate immune responses by recognizing pathogenic microorganisms, followed by a fine-tuned production of cytokines, chemokines and antimicrobial peptides or proteins (AMPs). Patients with atopic dermatitis (AD) suffer from a defective permeability barrier which favors pathogen infection indicating that the permeability and antimicrobial barrier functions are interdependent. Several early studies showed that the inducible AMPs LL-37, HBD-2 and HBD-3 are expressed at lower levels in atopic skin compared to psoriatic skin. However, recent data indicate that AMP induction is not compromised in AD patients and that several AMPs are expressed at significantly higher amounts in AD compared to healthy skin. AD patients have an increased susceptibility to Staphylococcus aureus skin infection suggesting that AMP levels expressed by keratinocytes of AD patients might not be sufficient to combat pathogenic skin infection or that AMP function is disturbed. Increasing AMP expression in AD skin and repairing the skin barrier defect might have a therapeutic effect in AD patients enabling the skin to mount an enhanced response to pathogens. Copyright © 2011 S. Karger AG, Basel.

Lipp H.-P.,University of Tubingen
Mycoses | Year: 2011

Posaconazole represents an antifungal extended-spectrum triazole whose absolute bioavailability following oral drug administration is considerably variable. Special conditions including increased gastric pH values, malabsorption syndrome, diarrhoea, intake on an empty stomach and some concomitantly administered potent enzyme-inducing drugs may contribute to lower drug plasma levels than expected. As a consequence, establishment of Therapeutic Drug Monitoring (TDM) has been proposed to be beneficial in patients receiving antifungal prophylaxis or therapy with posaconazole. Based on its considerable CYP3A inhibiting potency, posaconazole may significantly increase plasma concentrations of concomitantly applied drugs which undergo an extensive first-pass effect through gut and liver. More intensified posaconazole TDM may help to estimate the extent of drug interaction more accurately. © 2011 Blackwell Verlag GmbH.

Maier W.,University of Tubingen
Journal of Mammalian Evolution | Year: 2013

It is accepted in the literature that the levator veli palatini muscle of artiodactyls originates at the ectotympanic bone, a statement based on macroscopic dissection of adult specimens. The study of 34 histological serial sections of fetal heads of 23 species of artiodactyls revealed that this generalization must be modified: in the studied Camelidae, Suidae, Hippopotamidae, Giraffidae, and in some Bovidae (namely Tragelaphus and Antidorcas) the primary attachment of this functionally important muscle is at the tendinous intersection with the tensor veli palatini. Primary ontogenetic attachments are considered as relevant for defining homologies. By outgroup comparison (Felis and Diceros), this structural connection (character state 1) is also found in the Scrotifera-and hence may be considered as plesiomorphic for the Artiodactyla and its subunits. Only in the Tragulidae, Cervidae, Moschidae, and some Bovidae is a secondary attachment at the ectotympanic observed, which is interpreted as apomorphic for these taxa; possibly this character state 2 developed homoplastically several times. Bovidae show a mixed distribution of this character: Tragelaphus, Aepyceros, and Antidorcas show only a connection of the levator with the tensor veli; in Neotragus, Raphicerus, and Sylvicapra there exists an additional insertion at the ectotympanic; only Bos, Cephalophus, Damaliscus, and Ovis have a primary origin at the ectotympanic. It can be demonstrated in late fetal Sus that a secondary insertion of the levator veli at the ectotympanic is established during ontogeny; in a late fetal Ovis a secondary contact with the tensor veli is realized. The interpretation of this character distribution depends not only on an intrinsic polarity ('Lesrichtung'), but also on the assumed character state of the groundplan of the common ancestor of the Bovidae. The anatomical observations are documented by photographs of relevant histological sections. The character states are mapped on a simplified and synoptic cladogram of extant artiodactyls; their pattern of evolutionary transformation as well as their relevance for the phylogenetic systematics of this mammalian order are discussed. © 2012 Springer Science+Business Media, LLC.

Lukes-Gerakopoulos G.,Friedrich - Schiller University of Jena | Seyrich J.,University of Tubingen | Kunst D.,University of Bremen
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2014

In this paper we report the results of a thorough numerical study of the motion of spinning particles in Kerr spacetime with different prescriptions. We first evaluate the Mathisson-Papapetrou equations with two different spin supplementary conditions, namely, the Tulczyjew and the Newton-Wigner, and make a comparison of these two cases. We then use the Hamiltonian formalism given by Barausse, Racine, and Buonanno [Phys. Rev. D 80, 104025 (2009)] to evolve the orbits and compare them with the corresponding orbits provided by the Mathisson-Papapetrou equations. We include a full description of how to treat the issues arising in the numerical implementation. © 2014 American Physical Society.

Bartels A.,University of Tubingen
Current Biology | Year: 2014

A new human fMRI study shows how early visual cortex makes sense of complex visual scenes by segregating foreground and background, and by highlighting outlier objects. The findings are consistent with two attractive theories: biased competition and predictive coding. © 2014 Elsevier Ltd.

Robinson D.G.,University of Heidelberg | Pimpl P.,University of Tubingen
Protoplasma | Year: 2014

In this article we challenge the widely accepted view that receptors for soluble vacuolar proteins (VSRs) bind to their ligands at the trans-Golgi network (TGN) and transport this cargo via clathrin-coated vesicles (CCV) to a multivesicular prevacuolar compartment. This notion, which we term the "classical model" for vacuolar protein sorting, further assumes that low pH in the prevacuolar compartment causes VSR-ligand dissociation, resulting in a retromer-mediated retrieval of the VSRs to the TGN. We have carefully evaluated the literature with respect to morphology and function of the compartments involved, localization of key components of the sorting machinery, and conclude that there is little direct evidence in its favour. Firstly, unlike mammalian cells where the sorting receptor for lysosomal hydrolases recognizes its ligand in the TGN, the available data suggests that in plants VSRs interact with vacuolar cargo ligands already in the endoplasmic reticulum. Secondly, the evidence supporting the packaging of VSR-ligand complexes into CCV at the TGN is not conclusive. Thirdly, the prevacuolar compartment appears to have a pH unsuitable for VSR-ligand dissociation and lacks the retromer core and the sorting nexins needed for VSR recycling. We present an alternative model for protein sorting in the TGN that draws attention to the much overlooked role of Ca2+ in VSR-ligand interactions and which may possibly also be a factor in the sequestration of secretory proteins. © 2013 Springer-Verlag Wien.

Illumination in natural scenes changes at multiple temporal and spatial scales: slow changes in global illumination occur in the course of a day, and we encounter fast and localised illumination changes when visually exploring the non-uniform light field of three-dimensional scenes; in addition, very long-term chromatic variations may come from the environment, like for example seasonal changes. In this context, I consider the temporal and spatial properties of chromatic adaptation and discuss their functional significance for colour constancy in three-dimensional scenes. A process of fast spatial tuning in chromatic adaptation is proposed as a possible sensory mechanism for linking colour constancy to the spatial structure of a scene. The observed middlewavelength selectivity of this process is particularly suitable for adaptation to the mean chromaticity and the compensation of interreflections in natural scenes. Two types of sensory colour constancy are distinguished, based on the functional differences of their temporal and spatial scales: a slow type, operating at a global scale for the compensation of the ambient illumination; and a fast colour constancy, which is locally restricted and well suited to compensate region-specific variations in the light field of three dimensional scenes. © 2014 Elsevier B.V.

Neumann M.,University of Tubingen | Neumann M.,German Center for Neurodegenerative Diseases
Revue Neurologique | Year: 2013

In the last years, new disease proteins and genes have been identified in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), leading to a dramatic shift in our understanding of the molecular mechanisms underlying both conditions. The vast majority of FTLD and ALS are characterized by the abnormal accumulation of TDP-43, including genetic forms associated with mutations in the genes C9ORF72, GRN, TARDBP and VCP. The overlap in pathology and of genetic factors, particularly C9ORF72 as common cause of ALS and FTLD, provides molecular evidence that both conditions represent a spectrum of diseases sharing similar pathomechanisms. Accumulation of the protein FUS defines another subset of FTLD and ALS. However, here some striking differences have been identified. All members of the FET family (FUS, EWS, TAF15) are co-accumulating with their nuclear import receptor Transportin in FTLD-FUS which is usually not associated with FUS mutations, whilst ALS-FUS is almost always associated with FUS mutations and reveals only FUS aggregates. Together with recent data demonstrating differences in the arginine methylation status of FUS in FTLD-FUS and ALS-FUS, these findings strongly imply at least partially distinct underlying disease mechanisms in these molecular subtypes of ALS and FTLD. © 2013 Elsevier Masson SAS.