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Rijeka, Croatia

The University of Rijeka is in the city of Rijeka with faculties in cities throughout the regions of Primorje, Istria and Lika. The University of Rijeka is composed of nine faculties, one art academy, four departments, university libraries and the Students Centre. Wikipedia.

We consider non-stationary 1-D flow of a compressible viscous heat-conducting micropolar fluid, assuming that it is in the thermodynamical sense perfect and polytropic. The homogeneous boundary conditions for velocity and microrotation, as well as non-homogeneous boundary conditions for temperature are introduced. This problem has a unique generalized solution locally in time. With the help of this result and using the principle of extension we prove a global-in-time existence theorem. © 2014 Elsevier Ltd. All rights reserved. Source

We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease γ-secretase, from the initial interaction with its C99 substrate to the final release of toxic Aβ peptides. The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aβ42/Aβ40 ratio is observed in pre-steady-state when Aβ40 is the dominant product. Aβ42 is produced after Aβ40, and therefore Aβ42 is not a precursor for Aβ40. The longer more hydrophobic Aβ products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of γ-secretase with its C99 substrate leads to 30% decrease in Aβ40 with concomitant increase in the longer Aβ products and Aβ42/Aβ40 ratio. To different degree the same changes in Aβ products can be observed with two mutations that lead to an early onset of AD, ΔE9 and G384A. Four different lines of evidence show that γ-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, NotchΔE substrate can activate or inhibit γ-secretase activity on C99 substrate. Multiple C99 molecules bound to γ-secretase can affect processive cleavages of the nascent Aβ catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded Aβ-bundles. Gradual saturation of γ-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of γ-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded Aβ-bundles generated by γ-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis. Source

Svedruzic Z.M.,University of Rijeka
Progress in Molecular Biology and Translational Science

Dnmt1, the principal DNA methyltransferase in mammalian cells, is a large and a highly dynamic enzyme with multiple regulatory features that can control DNA methylation in cells. This chapter highlights how insights into Dnmt1 structure and function can advance our understanding of DNA methylation in cells. The allosteric site(s) on Dnmt1 can regulate processes of de novo and maintenance DNA methylation in cells. Remaining open questions include which molecules, by what mechanism, bind at the allosteric site(s) in cells? Different phosphorylation sites on Dnmt1 can change its activity or ability to bind DNA target sites. Thirty-one different molecules are currently known to have physical and/or functional interaction with Dnmt1 in cells. The Dnmt1 structure and enzymatic mechanism offer unique insights into those interactions. The interacting molecules are involved in chromatin organization, DNA repair, cell cycle regulation, and apoptosis and also include RNA polymerase II, some RNA-binding proteins, and some specific Dnmt1-inhibitory RNA molecules. Combined insights from studies of different enzymatic features of Dnmt1 offer novel ideas for development of drug candidates, and can be used in selection of promising drug candidates from more than 15 different compounds that have been identified as possible inhibitors of DNA methylation in cells. © 2011 Elsevier Inc. Source

Domitrovic R.,University of Rijeka
Current Medicinal Chemistry

This review summarizes the current knowledge of the regulatory role of pure anthocyans in cellular signaling pathways and gene expression. The molecular basis for anthocyans pharmacological activity includes the regulation of plethora of mechanisms mainly involved in: (1) suppression of the inflammatory response through targeting the phospholipase A2 and PI3K/Akt and NF-κB pathways, (2) protection from cardiovascular disease by exerting (i) antihypertensive and endothelium-protective activity through targeting the Akt/eNOS and ACE pathways (ii) antiatherogenic activity through targeting NF-κB mediated VCAM and ICAM expression, (3) growth/differentiation control and tumor suppression by exerting (i) anticancerogenic activity through targeting the EGF and HGF signaling pathways (ii) tumor anti-invasive activity through targeting the VEGF signaling pathway and ECM degrading enzymes (iii) cell cycle arrest and induction of apoptosis through the JNK/p38 MAPK mediated caspase activation (iv) modulation of chemotherapeutic efficacy by affecting resistance to anticancer drugs, (4) reduction of diabetes incidence through modulation of insulin sensitivity and glucose utilization, (5) neuroprotection through amelioration of oxidative stress and Aκ deposition, and (6) hepatoprotective activity through interference with TNF-β and TGF-β in the liver. The estrogen-like activity of anthocyans could be utilized in cancer and hormone-replacement therapy. These data provide a concise insight into molecular mechanisms of protective and therapeutic activity of anthocyans in various pathological conditions, which may not be attributed solely to their antioxidant activity but also to direct blockage of signaling pathways. Structure-activity analysis reveals that the number of hydroxyl groups and presence of sugar moiety are crucial for their specific modulatory actions. © 2011 Bentham Science Publishers. Source

Van Swinderen B.,University of Queensland | Andretic R.,University of Rijeka
Proceedings of the Royal Society B: Biological Sciences

In mammals, the neurotransmitter dopamine (DA) modulates a variety of behaviours, although DA function is mostly associated with motor control and reward. In insects such as the fruitfly, Drosophila melanogaster, DA also modulates a wide array of behaviours, ranging from sleep and locomotion to courtship and learning. How can a single molecule play so many different roles? Adaptive changes within the DA system, anatomical specificity of action and effects on a variety of behaviours highlight the remarkable versatility of this neurotransmitter. Recent genetic and pharmacological manipulations of DA signalling in Drosophila have launched a surfeit of stories-each arguing for modulation of some aspect of the fly's waking (and sleeping) life. Although these stories often seem distinct and unrelated, there are some unifying themes underlying DA function and arousal states in this insect model. One of the central roles played by DA may involve perceptual suppression, a necessary component of both sleep and selective attention. © 2011 The Royal Society. Source

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