University of LjubljanaLjubljana

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University of LjubljanaLjubljana

Science, Slovenia
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Szalaj N.,Jagiellonian University | Bajda M.,Jagiellonian University | Dudek K.,Jagiellonian University | Brus B.,University of LjubljanaLjubljana | And 2 more authors.
Archiv der Pharmazie | Year: 2015

Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50=33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Pal B.,University of Cincinnati | Schwartz A.J.,University of Cincinnati | Abdesselam A.,University of Tabuk | Adachi I.,Graduate University for Advanced Studies | And 187 more authors.
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2015

We report a search for the charmless hadronic decay B0→ηπ0 with a data sample corresponding to an integrated luminosity of 694 fb-1 containing 753×106 BB¯ pairs. The data were collected by the Belle experiment running on the Y(4S) resonance at the KEKB e+e- collider. We measure a branching fraction B(B0→ηπ0)=(4.1-1.5-0.7+1.7+0.5)×10-7, where the first uncertainty is statistical and the second is systematic. Our measurement gives an upper limit of B(B0→ηπ0)<6.5×10-7 at 90% confidence level. The signal has a significance of 3.0 standard deviations and constitutes the first evidence for this decay mode. © 2015 American Physical Society. © 2015 American Physical Society.

Maneek-Keber M.,National Institute of ChemistryLjubljana | Frank-Bertoncelj M.,University Medical Center LjubljanaLjubljana | Hafner-Bratkovie I.,National Institute of ChemistryLjubljana | Smole A.,National Institute of ChemistryLjubljana | And 9 more authors.
Science Signaling | Year: 2015

Oxidative stress produced in response to infection or sterile injury activates the innate immune response. We found that extracellular vesicles (EVs) isolated from the plasma of patients with rheumatoid arthritis or secreted from cells subjected to oxidative stress contained oxidized phospholipids that stimulated cells expressing Toll-like receptor 4 (TLR4) in a manner dependent on its co-receptor MD-2. EVs from healthy subjects or reconstituted synthetic EVs subjected to limited oxidation gained the ability to stimulate TLR4-expressing cells, whereas prolonged oxidation abrogated this property. Furthermore, we found that 15-lipoxygenase generated hydro(pero)xylated phospholipids that stimulated TLR4-expressing cells. Molecular modeling suggested that the mechanism of activation of TLR4 by oxidized phospholipids in EVs was structurally similar to that of the TLR4 ligand lipopolysaccharide (LPS). This was supported by experiments showing that EV-mediated stimulation of cells required MD-2, that mutations that block LPS binding to TLR4 abrogated the stimulatory effect of EVs, and that EVs induced TLR4 dimerization. On the other hand, analysis of gene expression profiles showed that genes encoding factors that resolve inflammation were more abundantly expressed in responses to EVs than in response to LPS. Together, these data suggest that EVs act as an oxidative stress-induced endogenous danger signal that underlies the pervasive role of TLR4 in inflammatory diseases.

Zhao Y.X.,Hefei University of Technology | Allada K.,Massachusetts Institute of Technology | Allada K.,Jefferson Lab | Aniol K.,California State University, Los Angeles | And 127 more authors.
Physical Review C - Nuclear Physics | Year: 2015

We report the measurement of beam-target double spin asymmetries (A LT) in the inclusive production of identified hadrons, e + 3 He → h + X, using a longitudinally polarized 5.9-GeV electron beam and a transversely polarized He 3 target. Hadrons (π ±, K ±, and proton) were detected at 16 with an average momentum P h = 2.35 GeV/c and a transverse momentum (p T) coverage from 0.60 to 0.68 GeV/c. Asymmetries from the He 3 target were observed to be nonzero for π ± production when the target was polarized transversely in the horizontal plane. The π + and π - asymmetries have opposite signs, analogous to the behavior of A LT in semi-inclusive deep-inelastic scattering. © 2015 American Physical Society.

Tabernik D.,University of LjubljanaLjubljana | Leonardis A.,University of LjubljanaLjubljana | Leonardis A.,University of Birmingham | Boben M.,University of LjubljanaLjubljana | And 2 more authors.
Computer Vision and Image Understanding | Year: 2015

Abstract In this paper we identify two types of problems with excessive feature sharing and the lack of discriminative learning in hierarchical compositional models: (a) similar category misclassifications and (b) phantom detections in background objects. We propose to overcome those issues by fully utilizing a discriminative features already present in the generative models of hierarchical compositions. We introduce descriptor called histogram of compositions to capture the information important for improving discriminative power and use it with a classifier to learn distinctive features important for successful discrimination. The generative model of hierarchical compositions is combined with the discriminative descriptor by performing hypothesis verification of detections produced by the hierarchical compositional model. We evaluate proposed descriptor on five datasets and show to improve the misclassification rate between similar categories as well as the misclassification rate of phantom detections on backgrounds. Additionally, we compare our approach against a state-of-the-art convolutional neural network and show to outperform it under significant occlusions. © 2015 Elsevier Inc.

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