Design, synthesis and evaluation of a tripodal receptor for phosphatidylinositol phosphates

Phosphatidylinositol phosphates (PIPs) are membrane phospholipids that play crucial roles in a wide range of cellular processes. Their function is dictated by the number and positions of the phosphate groups in the inositol ring (with seven different PIPs being active in the cell). Therefore, there is significant interest in developing small-molecule receptors that can bind selectively to these species and in doing so affect their cellular function or be the basis for molecular probes. However, to date there are very few examples of such molecular receptors. Towards this aim, herein we report a novel tripodal molecule that acts as receptor for mono- and bis-phosphorylated PIPs in a cell free environment. To assess their affinity to PIPs we have developed a new cell free assay based on the ability of the receptor to prevent alkaline phosphatase from hydrolysing these substrates. The new receptor displays selectivity towards two out of the seven PIPs, namely PI(3)P and PI(3,4)P2. To rationalise these results, a DFT computational study was performed which corroborated the experimental results and provided insight into the host–guest binding mode

Unitary Positive-Energy Representations of Scalar Bilocal Quantum Fields

The superselection sectors of two classes of scalar bilocal quantum fields in D>=4 dimensions are explicitly determined by working out the constraints imposed by unitarity. The resulting classification in terms of the dual of the respective gauge groups U(N) and O(N) confirms the expectations based on general results obtained in the framework of local nets in algebraic quantum field theory, but the approach using standard Lie algebra methods rather than abstract duality theory is complementary. The result indicates that one does not lose interesting models if one postulates the absence of scalar fields of dimension D-2 in models with global conformal invariance. Another remarkable outcome is the observation that, with an appropriate choice of the Hamiltonian, a Lie algebra embedded into the associative algebra of observables completely fixes the representation theory.Comment: 27 pages, v3: result improved by eliminating redundant assumptio

Thermodynamics of Heat Shock Response

Production of heat shock proteins are induced when a living cell is exposed to a rise in temperature. The heat shock response of protein DnaK synthesis in E.coli for temperature shifts from temperature T to T plus 7 degrees, respectively to T minus 7 degrees is measured as function of the initial temperature T. We observe a reversed heat shock at low T. The magnitude of the shock increases when one increase the distance to the temperature $T_0 \approx 23^o$, thereby mimicking the non monotous stability of proteins at low temperature. Further we found that the variation of the heat shock with T quantitatively follows the thermodynamic stability of proteins with temperature. This suggest that stability related to hot as well as cold unfolding of proteins is directly implemented in the biological control of protein folding. We demonstrate that such an implementation is possible in a minimalistic chemical network.Comment: To be published in Physical Review Letter

Hyperentangled States

We investigate a new class of entangled states, which we call 'hyperentangled',that have EPR correlations identical to those in the vacuum state of a relativistic quantum field. We show that whenever hyperentangled states exist in any quantum theory, they are dense in its state space. We also give prescriptions for constructing hyperentangled states that involve an arbitrarily large collection of systems.Comment: 23 pages, LaTeX, Submitted to Physical Review

Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation. RESULTS: In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH(-/-) mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH(-/-) mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice. CONCLUSION: Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.Peer Reviewe

Future research demands of the United European Gastroenterology (UEG) and its member societies

AIMS: The purpose of this study was to initiate and stimulate collaborative research efforts to support United European Gastroenterology Federation (UEG) member societies facilitating digestive health research in European on the one hand and, on the other hand, to increase EU-funded digestive health research by providing evidence and advice to funding bodies on priority areas. The UEG Research Committee initiated a survey of the current and future research interests of each individual UEG ordinary member society (specialist societies). METHODS: A questionnaire was sent by mail to 17 UEG ordinary member societies asking them to specify research demands related to the most urgent medical need including basic science research, translational research, clinical research, patient management research and research on disease prevention, in an open fashion but with limited word count. RESULTS: The responses from 13 societies were analysed in a semi-quantitative and in a qualitative way, and were clustered into five domains with two aspects each that were consented and shared between three and seven of the responding 13 societies. These clusters resemble topics such as ‘Hot topics’ (e.g. life-style, nutrition, microbial-host interaction), Biomarkers (genetic profiling, gut-brain interaction), Advanced technology (artificial intelligence, personalised medicine), Global research tools (bio-banking, EU trials), and Medical training (education, prevention). CONCLUSION: The generated topic list allows both collaboration between individual specialist societies as well as initiating and fostering future research calls at the EU level and beyond when approaching stakeholders

Developed turbulence: From full simulations to full mode reductions

Developed Navier-Stokes turbulence is simulated with varying wavevector mode reductions. The flatness and the skewness of the velocity derivative depend on the degree of mode reduction. They show a crossover towards the value of the full numerical simulation when the viscous subrange starts to be resolved. The intermittency corrections of the scaling exponents of the pth order velocity structure functions seem to depend mainly on the proper resolution of the inertial subrange. Universal scaling properties (i.e., independent of the degree of mode reduction) are found for the relative scaling exponents rho which were recently defined by Benzi et al.Comment: 4 pages, 5 eps-figures, replaces version from August 5th, 199

Optimale Blockauswahl bei der Kraftwerkseinsatzplanung der VEAG

In der vorliegenden Arbeit beschreiben wir einen LP-basierten Branch-and-Bound- und einen Lagrange-Relaxations-Zugang für das Blockauswahlproblem in der Kraftwerkseinsatzplanung, wobei moderne Ansätze und Algorithmen für die entstehenden Teilprobleme zum Einsatz kommen. Für das zugrundeliegende Erzeugersystem aus thermischen Kraftwerken und Pumpspeicherwerken wurde ein gemischt-ganzzahliges lineares Optimierungsmodell entwickelt. Berichtet wird über Testrechnungen für dieses Modell in der mittelfristigen Planung zunächst mit Zeiträumen bis zu sechs Monaten

A geometrical origin for the covariant entropy bound

Causal diamond-shaped subsets of space-time are naturally associated with operator algebras in quantum field theory, and they are also related to the Bousso covariant entropy bound. In this work we argue that the net of these causal sets to which are assigned the local operator algebras of quantum theories should be taken to be non orthomodular if there is some lowest scale for the description of space-time as a manifold. This geometry can be related to a reduction in the degrees of freedom of the holographic type under certain natural conditions for the local algebras. A non orthomodular net of causal sets that implements the cutoff in a covariant manner is constructed. It gives an explanation, in a simple example, of the non positive expansion condition for light-sheet selection in the covariant entropy bound. It also suggests a different covariant formulation of entropy bound.Comment: 20 pages, 8 figures, final versio

Boundary conditions in the Unruh problem

We have analyzed the Unruh problem in the frame of quantum field theory and have shown that the Unruh quantization scheme is valid in the double Rindler wedge rather than in Minkowski spacetime. The double Rindler wedge is composed of two disjoint regions ($R$- and $L$-wedges of Minkowski spacetime) which are causally separated from each other. Moreover the Unruh construction implies existence of boundary condition at the common edge of $R$- and $L$-wedges in Minkowski spacetime. Such boundary condition may be interpreted as a topological obstacle which gives rise to a superselection rule prohibiting any correlations between $r$- and $l$- Unruh particles. Thus the part of the field from the $L$-wedge in no way can influence a Rindler observer living in the $R$-wedge and therefore elimination of the invisible "left" degrees of freedom will take no effect for him. Hence averaging over states of the field in one wedge can not lead to thermalization of the state in the other. This result is proved both in the standard and algebraic formulations of quantum field theory and we conclude that principles of quantum field theory does not give any grounds for existence of the "Unruh effect".Comment: 31 pages,1 figur