126 research outputs found

    WHO-IS: Wireless Hetnet Optimization using Impact Selection

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    We propose a method to first identify users who have the most negative impact on the overall network performance, and then offload them to an orthogonal channel. The feasibility of such an approach is verified using real-world traces, network simulations, and a lab experiment that employs multi-homed wireless stations. In our experiment, as offload target, we employ LiFi IR transceivers, and as the primary network we consider a typical Enterprise Wi-Fi setup. We found that a limited number of users can impact the overall experience of the Wi-Fi network negatively, hence motivating targeted offloading. In our simulations and experiments we saw that the proposed solution can improve the collision probability with 82% and achieve a 61 percentage point air utilization improvement compared to random offloading, respectively

    Evaluation of [F-18]F-DPA as a target for TSPO in head and neck cancer under normal conditions and after radiotherapy

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    Background Many malignant tumours have increased TSPO expression, which has been related to a poor prognosis. TSPO-PET tracers have not comprehensively been evaluated in peripherally located tumours. This study aimed to evaluate whether N,N-diethyl-2-(2-(4-([F-18]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([F-18]F-DPA) can reflect radiotherapy (RT)-induced changes in TSPO activity in head and neck squamous cell carcinoma (HNSCC). Methods RT was used to induce inflammatory responses in HNSCC xenografts and cells. [F-18]F-DPA uptake was measured in vivo in non-irradiated and irradiated tumours, followed by ex vivo biodistribution, autoradiography, and radiometabolite analysis. In vitro studies were performed in parental and TSPO-silenced (TSPO siRNA) cells. TSPO protein and mRNA expression, as well as tumour-associated macrophages (TAMs), were also assessed. Results In vivo imaging and ex vivo measurement revealed significantly higher [F-18]F-DPA uptake in irradiated, compared to non-irradiated tumours. In vitro labelling studies with cells confirmed this finding, whereas no effect of RT on [F-18]F-DPA uptake was detected in TSPO siRNA cells. Radiometabolite analysis showed that the amount of unchanged [F-18]F-DPA in tumours was 95%, also after irradiation. PK11195 pre-treatment reduced the tumour-to-blood ratio of [F-18]F-DPA by 73% in xenografts and by 88% in cells. TSPO protein and mRNA levels increased after RT, but were highly variable. The proportion of M1/M2 TAMs decreased after RT, whereas the proportion of monocytes and migratory monocytes/macrophages increased. Conclusions [F-18]F-DPA can detect changes in TSPO expression levels after RT in HNSCC, which does not seem to reflect inflammation. Further studies are however needed to clarify the physiological mechanisms regulated by TSPO after RT

    Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of őĪ-Amino-3- hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

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    Based on the activity of 1,2,4-benzothiadiazine 1,1-dioxides as AMPAR-PAMs, thiochroman 1,1-dioxides were designed apply- ing the isosteric replacement concept. The new compounds expressed a strong modulatory activity on AMPARs in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was exam- ined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallisation of the racemic compound 12b in complex with GluA2-LBD (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2-LBD dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (4). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D finger- print) and compared to those of 4. Taken together, these data explain the lower affinity on AMPARs of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides

    Binding of a negative allosteric modulator and competitive antagonist can occur simultaneously at the ionotropic glutamate receptor GluA2

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    Ionotropic glutamate receptors are ligand-gated ion channels governing neurotransmission in the central nervous system. Three major types of antagonists are known for the AMPA-type receptor GluA2: competitive, non-competitive (i.e. negative allosteric modulators; NAMs) used for treatment of epilepsy, and uncompetitive antagonists. We here report a 4.65 √Ö resolution X-ray structure of GluA2, revealing that four molecules of the competitive antagonist ZK200775 and four molecules of the NAM GYKI53655 are capable of binding at the same time. Using negative stain electron microscopy, we show that GYKI53655 alone or ZK200775/GYKI53655 in combination predominantly result in compact receptor forms. The agonist AMPA provides a mixed population of compact and bulgy shapes of GluA2 not impacted by addition of GYKI53655. Taken together, this suggests that the two different mechanisms of antagonism that lead to channel closure are independent and that the distribution between bulgy and compact receptors primarily depends on the ligand bound in the glutamate binding site

    Strong Nash equilibria and mixed strategies

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    We study strong Nash equilibriain mixed strategies in finite games. A Nash equilibrium is strong if no coalition of players can jointly deviate so that all players in the coalition get strictly better payoffs. Our main result concerns games with two players and states that if a game admits a strong Nash equilibrium, then the payoff pairs in the support of the equilibrium lie on a straight line in the players’ utility space. As a consequence, the set of games that have a strong Nash equilibrium in which at least one player plays a mixed strategy has measure zero. We show that the same property holds for games with more than two players, already when no coalition of two players can profitably deviate. Furthermore, we show that, in contrast to games with two players, in a strong Nash equilibrium an outcome that is strictly Pareto dominated may occur with positive probability

    A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

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    dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe
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