Showing papers by "University of Rijeka published in 2016"

NKG2D ligands mediate immunosurveillance of senescent cells

Abstract: Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.

Lay Definitions of Happiness across Nations: The Primacy of Inner Harmony and Relational Connectedness

Abstract: In well-being research the term happiness is often used as synonymous with life satisfaction. However, little is known about lay people’s understanding of happiness. Building on the available literature, this study explored lay definitions of happiness across nations and cultural dimensions, analyzing their components and relationship with participants’ demographic features. Participants were 2799 adults (age range=30-60, 50% women) living in urban areas of Argentina, Brazil, Croatia, Hungary, India, Italy, Mexico, New Zealand, Norway, Portugal, South Africa and United States. They completed the Eudaimonic and Hedonic Happiness Investigation (EHHI), reporting, among other information, their own definition of happiness. Answers comprised definitions referring to a broad range of life domains, covering both the contextual-social sphere and the psychological sphere. Across countries and with little variation by age and gender, inner harmony predominated among psychological definitions, and family and social relationships among contextual definitions. Whereas relationships are widely acknowledged as basic happiness components, inner harmony is substantially neglected. Nevertheless, its cross-national primacy, together with relations, is consistent with the view of an ontological interconnectedness characterizing living systems, shared by several conceptual frameworks across disciplines and cultures. At the methodological level, these findings suggest the potential of a bottom-up, mixed method approach to contextualize psychological dimensions within culture and lay understanding.

From Erythromycin to Azithromycin and New Potential Ribosome-Binding Antimicrobials.

Abstract: Macrolides, as a class of natural or semisynthetic products, express their antibacterial activity primarily by reversible binding to the bacterial 50S ribosomal subunits and by blocking nascent proteins’ progression through their exit tunnel in bacterial protein biosynthesis. Generally considered to be bacteriostatic, they may also be bactericidal at higher doses. The discovery of azithromycin from the class of macrolides, as one of the most important new drugs of the 20th century, is presented as an example of a rational medicinal chemistry approach to drug design, applying classical structure-activity relationship that will illustrate an impressive drug discovery success story. However, the microorganisms have developed several mechanisms to acquire resistance to antibiotics, including macrolide antibiotics. The primary mechanism for acquiring bacterial resistance to macrolides is a mutation of one or more nucleotides from the binding site. Although azithromycin is reported to show different, two-step process of the inhibition of ribosome function of some species, more detailed elaboration of that specific mode of action is needed. New macrocyclic derivatives, which could be more potent and less prone to escape bacterial resistance mechanisms, are also continuously evaluated. A novel class of antibiotic compounds—macrolones, which are derived from macrolides and comprise macrocyclic moiety, linker, and either free or esterified quinolone 3-carboxylic group, show excellent antibacterial potency towards key erythromycin-resistant Gram-positive and Gram-negative bacterial strains, with possibly decreased potential of bacterial resistance to macrolides.

HLA class II sequence variants influence tuberculosis risk in populations of European ancestry

Abstract: Mycobacterium tuberculosis infections cause 9 million new tuberculosis cases and 1.5 million deaths annually. To identify variants conferring risk of tuberculosis, we tested 28.3 million variants identified through whole-genome sequencing of 2,636 Icelanders for association with tuberculosis (8,162 cases and 277,643 controls), pulmonary tuberculosis (PTB) and M. tuberculosis infection. We found association of three variants in the region harboring genes encoding the class II human leukocyte antigens (HLAs): rs557011[T] (minor allele frequency (MAF) = 40.2%), associated with M. tuberculosis infection (odds ratio (OR) = 1.14, P = 3.1 × 10(-13)) and PTB (OR = 1.25, P = 5.8 × 10(-12)), and rs9271378[G] (MAF = 32.5%), associated with PTB (OR = 0.78, P = 2.5 × 10(-12))--both located between HLA-DQA1 and HLA-DRB1--and a missense variant encoding p.Ala210Thr in HLA-DQA1 (MAF = 19.1%, rs9272785), associated with M. tuberculosis infection (P = 9.3 × 10(-9), OR = 1.14). We replicated association of these variants with PTB in samples of European ancestry from Russia and Croatia (P < 5.9 × 10(-4)). These findings show that the HLA class II region contributes to genetic risk of tuberculosis, possibly through reduced presentation of protective M. tuberculosis antigens to T cells.

How can we improve antibiotic prescribing in primary care

Abstract: Antibiotic stewardship is a necessity given the worldwide antimicrobial resistance crisis. Outpatient antibiotic use represents around 90% of total antibiotic use, with more than half of these prescriptions being either unnecessary or inappropriate. Efforts to improve antibiotic prescribing need to incorporate two complementary strategies: changing healthcare professionals' behaviour, and modifying the healthcare system. In this review, we present a broad perspective on antibiotic stewardship in primary care in high and high-middle income country settings, focussing on studies published in the last five years. We present the limitations of available literature, discuss perspectives, and provide suggestions for where future work should be concentrated.

Minimally invasive, non-ablative Er:YAG laser treatment of stress urinary incontinence in women—a pilot study

Abstract: The study presents an assessment of mechanism of action and a pilot clinical study of efficacy and safety of the Er:YAG laser for the treatment of stress urinary incontinence (SUI). The subject of this study is a treatment of SUI with a 2940 nm Er:YAG laser, operating in a special SMOOTH mode designed to increase temperature of the vaginal mucosa up to maximally 60–65 °C without ablating the epidermis. Numerical modelling of the temperature distribution within mucosa tissue following an irradiation with the SMOOTH mode Er:YAG laser was performed in order to determine the appropriate range of laser parameters. The laser treatment parameters were further confirmed by measuring in vivo temperatures of the vaginal mucosa using a thermal camera. To investigate the clinical efficacy and safety of the SMOOTH mode Er:YAG laser SUI treatment, a pilot clinical study was performed. The study recruited 31 female patients suffering from SUI. Follow-ups were scheduled at 1, 2, and 6 months post treatment. ICIQ-UI questionnaires were collected as a primary trial endpoint. Secondary endpoints included perineometry and residual urine volume measurements at baseline and all follow-ups. Thermal camera measurements have shown the optimal increase in temperature of the vaginal mucosa following treatment of SUI with a SMOOTH mode Er:YAG laser. Primary endpoint, the change in ICIQ-UI score, showed clinically relevant and statistically significant improvement after all follow-ups compared to baseline scores. There was also improvement in the secondary endpoints. Only mild and transient adverse events and no serious adverse events were reported. The results indicate that non-ablative Er:YAG laser therapy is a promising minimally invasive non-surgical option for treating women with SUI symptoms.

Multiwavelength Study Of Quiescent States Of Mrk 421 With Unprecedented Hard X-Ray Coverage Provided By Nustar In 2013

Abstract: We present coordinated multiwavelength observations of the bright, nearby BL Lacertae object Mrk 421 taken in 2013 January–March, involving GASP-WEBT, Swift, NuSTAR, Fermi-LAT, MAGIC, VERITAS, and other collaborations and instruments, providing data from radio to very high energy (VHE) γ-ray bands. NuSTAR yielded previously unattainable sensitivity in the 3–79 keV range, revealing that the spectrum softens when the source is dimmer until the X-ray spectral shape saturates into a steep Γ ≈ 3 power law, with no evidence for an exponential cutoff or additional hard components up to ~80 keV. For the first time, we observed both the synchrotron and the inverse-Compton peaks of the spectral energy distribution (SED) simultaneously shifted to frequencies below the typical quiescent state by an order of magnitude. The fractional variability as a function of photon energy shows a double-bump structure that relates to the two bumps of the broadband SED. In each bump, the variability increases with energy, which, in the framework of the synchrotron self-Compton model, implies that the electrons with higher energies are more variable. The measured multi band variability, the significant X-ray-to-VHE correlation down to some of the lowest fluxes ever observed in both bands, the lack of correlation between optical/UV and X-ray flux, the low degree of polarization and its significant (random) variations, the short estimated electron cooling time, and the significantly longer variability timescale observed in the NuSTAR light curves point toward in situ electron acceleration and suggest that there are multiple compact regions contributing to the broadband emission of Mrk 421 during low-activity states.

Cytomegalovirus pUL50 is the multi-interacting determinant of the core nuclear egress complex (NEC) that recruits cellular accessory NEC components.

Abstract: Nuclear egress of herpesvirus capsids through the nuclear envelope is mediated by the multimeric nuclear egress complex (NEC). The human cytomegalovirus (HCMV) core NEC is defined by an interaction between the membrane-anchored pUL50 and its nuclear co-factor pUL53, tightly associated through heterodimeric corecruitment to the nuclear envelope. Cellular proteins, such as p32/gC1qR, emerin and protein kinase C (PKC), are recruited by direct interaction with pUL50 for the multimeric extension of the NEC. As a functionally important event, the recruitment of both viral and cellular protein kinases leads to site-specific lamin phosphorylation and nuclear lamina disassembly. In this study, interaction domains within pUL50 for its binding partners were defined by co-immunoprecipitation. The interaction domain for pUL53 is located within the pUL50 N-terminus (residues 10-169), interaction domains for p32/gC1qR (100-358) and PKC (100-280) overlap in the central part of pUL50, and the interaction domain for emerin is located in the C-terminus (265-397). Moreover, expression and formation of core NEC proteins at the nuclear rim were consistently detected in cells permissive for productive HCMV replication, including two trophoblast-cell lines. Importantly, regular nuclear-rim formation of the core NEC was blocked by inhibition of cyclin-dependent kinase (CDK) activity. In relation to the recently published crystal structure of the HCMV core NEC, our findings result in a refined view of NEC assembly. In particular, we suggest that CDKs may play an important regulatory role in NEC formation during HCMV replication.

A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives.

Abstract: Hepatoprotective effects of natural compounds have been frequently attributed to their antioxidant properties and the ability to mobilize endogenous antioxidant defense system. Because of involvement of oxidative stress in virtually all mechanisms of liver injury, it is a reasonable presumption that antioxidant properties of these compounds may play a key role in the mechanism of their hepatoprotective activity. Nevertheless, growing evidence suggests that other pharmacological activities of natural compounds distinct from antioxidant are responsible for their therapeutic effects. In this review, we discussed currently known molecular mechanisms of the hepatoprotective activity of 27 most intensively studied phytochemicals. These compounds have been shown to possess anti-inflammatory, antisteatotic, antiapoptotic, cell survival and antiviral activity through interference with multiple molecular targets and signaling pathways. Additionally, antifibrotic properties of phytochemicals have been closely associated with apoptosis of hepatic stellate cells and stimulation of extracellular matrix degradation. However, although these compounds exhibit a pronounced hepatoprotective effects in animal and cell culture models, the lack of clinical studies remains a bottleneck for their official acceptance by medical experts and physicians. Therefore, controlled clinical trials have an imperative in confirmation of the therapeutic activity of potentially hepatoprotective compounds. Understanding the principles of the hepatoprotective activity of phytochemicals could guide future drug development and help prevention of clinical trial failure. Also, the use of new delivery systems that enhances bioavailability of poorly water soluble compounds may improve the results already obtained. Most importantly, available data suggest that phytochemicals possess a various degree of modulation of specific signaling pathways, pointing out a need for usage of combinations of several hepatoprotective compounds in both experimental studies and clinical trials.

Teraelectronvolt pulsed emission from the Crab pulsar detected by MAGIC

Abstract: Aims. We investigate the extension of the very high-energy spectral tail of the Crab Pulsar at energies above 400 GeV. Methods. We analyzed ~320 h of good-quality Crab data obtained with the MAGIC telescope from February 2007 to April 2014. Results. We report the most energetic pulsed emission ever detected from the Crab Pulsar reaching up to 1.5 TeV. The pulse profile shows two narrow peaks synchronized with those measured in the GeV energy range. The spectra of the two peaks follow two different power-law functions from 70 GeV up to 1.5 TeV and connect smoothly with the spectra measured above 10 GeV by the Large Area Telescope (LAT) on board the Fermi satellite. When making a joint fit of the LAT and MAGIC data above 10 GeV the photon indices of the spectra differ by 0.5 ± 0.1. Conclusions. Using data from the MAGIC telescopes we measured the most energetic pulsed photons from a pulsar to date. Such TeV pulsed photons require a parent population of electrons with a Lorentz factor of at least 5 × 106. These results strongly suggest IC scattering off low-energy photons as the emission mechanism and a gamma-ray production region in the vicinity of the light cylinder.

The First Circumbinary Planet Found by Microlensing: OGLE-2007-BLG-349L(AB)c

Abstract: © 2016. The American Astronomical Society. All rights reserved.We present the analysis of the first circumbinary planet microlensing event, OGLE-2007-BLG-349. This event has a strong planetary signal that is best fit with a mass ratio of q ≈ 3.4 × 10-4, but there is an additional signal due to an additional lens mass, either another planet or another star. We find acceptable light-curve fits with two classes of models: two-planet models (with a single host star) and circumbinary planet models. The light curve also reveals a significant microlensing parallax effect, which constrains the mass of the lens system to be M L ≈ 0.7 M⊙. Hubble Space Telescope (HST) images resolve the lens and source stars from their neighbors and indicate excess flux due to the star(s) in the lens system. This is consistent with the predicted flux from the circumbinary models, where the lens mass is shared between two stars, but there is not enough flux to be consistent with the two-planet, one-star models. So, only the circumbinary models are consistent with the HST data. They indicate a planet of mass m c = 80 ± 13 M⊙, orbiting a pair of M dwarfs with masses of M A = 0.41 ± 0.07 and M B = 0.30 ± 0.07, which makes this the lowest-mass circumbinary planet system known. The ratio of the separation between the planet and the center of mass to the separation of the two stars is ∼40, so unlike most of the circumbinary planets found by Kepler, the planet does not orbit near the stability limit.

Renal replacement therapy in Europe: a summary of the 2013 ERA-EDTA Registry Annual Report with a focus on diabetes mellitus

Abstract: Background This article provides a summary of the 2013 European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report (available at http://www.era-edta-reg.org), with a focus on patients with diabetes mellitus (DM) as the cause of end-stage renal disease (ESRD).

Impact of global economic crisis on firm growth

Abstract: The global economic crisis has had an adverse effect on, and may continue to affect, the entrepreneurial sector all over the world. However, even in a recessionary period, there will always be some firms growing faster than others. It is therefore imperative to understand the variables and processes that make some firms grow faster or more resilient to crisis than others. In this paper, we focus on firm size and its contributions to growth. We examine whether growth rates of manufacturing and service industries are independent of firm size during the period of economic crisis. Based on a large sample of surviving firms in the manufacturing and hospitality industries, the results of two-step dynamic panel suggest that turnover growth is positively associated with companies’ size during the observed period of economic recession 2008–2013. In both industries, large and medium-sized firms exhibit higher growth than do small firms.

Recommender System and Web 2.0 Tools to Enhance a Blended Learning Model

Abstract: Blended learning models that combine face-to-face and online learning are of great importance in modern higher education. However, their development should be in line with the recent changes in e-learning that emphasize a student-centered approach and use tools available on the Web to support the learning process. This paper presents research on implementing a contemporary blended learning model within the e-course “Hypermedia Supported Education”. The blended model developed combines a learning management system (LMS), a set of Web 2.0 tools and the E-Learning Activities Recommender System (ELARS) to enhance personalized online learning. As well as incorporating various technologies, the model combines a number of pedagogical approaches, focusing on collaborative and problem-based learning, to ensure the achievement of the course learning outcomes. The results of the comparative study show the effectiveness of the proposed model in that students who performed personalized collaborative e-learning activities achieved better course results. These findings encourage the further application of the model to other computer science courses.

Extracellular vesicles in blood, milk and body fluids of the female and male urogenital tract and with special regard to reproduction

Abstract: Extracellular vesicles (EVs) are released from almost all cells and tissues. They are able to transport substances (e.g. proteins, RNA or DNA) at higher concentrations than in their environment and may adhere in a receptor-controlled manner to specific cells or tissues in order to release their content into the respective target structure. Blood contains high concentrations of EVs mainly derived from platelets, and, at a smaller amount, from erythrocytes. The female and male reproductive tracts produce EVs which may be associated with fertility or infertility and are released into body fluids and mucosas of the urogenital organs. In this review, the currently relevant detection methods are presented and critically compared. During pregnancy, placenta-derived EVs are dynamically detectable in peripheral blood with changing profiles depending upon progress of pregnancy and different pregnancy-associated pathologies, such as preeclampsia. EVs offer novel non-invasive diagnostic tools which may reflect the situation of the placenta and the foetus. EVs in urine have the potential of reflecting urogenital diseases including cancers of the neighbouring organs. Several methods for detection, quantification and phenotyping of EVs have been established, which include electron microscopy, flow cytometry, ELISA-like methods, Western blotting and analyses based on Brownian motion. This review article summarises the current knowledge about EVs in blood and cord blood, in the different compartments of the male and female reproductive tracts, in trophoblast cells from normal and pre-eclamptic pregnancies, in placenta ex vivo perfusate, in the amniotic fluid, and in breast milk, as well as their potential effects on natural killer cells as possible targets.

Oral pathology in inflammatory bowel disease

Abstract: The incidence of inflammatory bowel diseases (IBD) - Crohn's disease (CD) and ulcerative colitis (UC) - has been increasing on a global scale, and progressively, more gastroenterologists will be included in the diagnosis and treatment of IBD. Although IBD primarily affects the intestinal tract, extraintestinal manifestations of the disease are often apparent, including in the oral cavity, especially in CD. Specific oral manifestations in patients with CD are as follows: indurate mucosal tags, cobblestoning and mucogingivitis, deep linear ulcerations and lip swelling with vertical fissures. The most common non-specific manifestations, such as aphthous stomatitis and angular cheilitis, occur in both diseases, while pyostomatitis vegetans is more pronounced in patients with UC. Non-specific lesions in the oral cavity can also be the result of malnutrition and drugs. Malnutrition, followed by anemia and mineral and vitamin deficiency, affects the oral cavity and teeth. Furthermore, all of the drug classes that are applied to the treatment of inflammatory bowel diseases can lead to alterations in the oral cavity due to the direct toxic effects of the drugs on oral tissues, as well as indirect immunosuppressive effects with a risk of developing opportunistic infections or bone marrow suppression. There is a higher occurrence of malignant diseases in patients with IBD, which is related to the disease itself and to the IBD-related therapy with a possible oral pathology. Treatment of oral lesions includes treatment of the alterations in the oral cavity according to the etiology together with treatment of the primary intestinal disease, which requires adequate knowledge and a strong cooperation between gastroenterologists and specialists in oral medicine.

The Golgi apparatus acts as a platform for TBK1 activation after viral RNA sensing.

Abstract: After viral infection and the stimulation of some pattern-recognition receptors, TANK-binding kinase I (TBK1) is activated by K63-linked polyubiquitination followed by trans-autophosphorylation. While the activated TBK1 induces type I interferon production by phosphorylating the transcription factor IRF3, the precise molecular mechanisms underlying TBK1 activation remain unclear. We report here the localization of the ubiquitinated and phosphorylated active form of TBK1 to the Golgi apparatus after the stimulation of RIG-I-like receptors (RLRs) or Toll-like receptor-3 (TLR3), due to TBK1 K63-linked ubiquitination on lysine residues 30 and 401. The ubiquitin-binding protein optineurin (OPTN) recruits ubiquitinated TBK1 to the Golgi apparatus, leading to the formation of complexes in which TBK1 is activated by trans-autophosphorylation. Indeed, OPTN deficiency in various cell lines and primary cells impairs TBK1 targeting to the Golgi apparatus and its activation following RLR or TLR3 stimulation. Interestingly, the Bluetongue virus NS3 protein binds OPTN at the Golgi apparatus, neutralizing its activity and thereby decreasing TBK1 activation and downstream signaling. Our results highlight an unexpected role of the Golgi apparatus in innate immunity as a key subcellular gateway for TBK1 activation after RNA virus infection.

What makes classification trees comprehensible

Abstract: In-depth survey for empirical study of the classification-tree comprehensibility.Objective measurements suggest the most influential parameter: the depth of leaves.Number of leaves is a relevant comprehensibility measure only for complex trees.Tree visualization style and layout significantly influence the comprehensibility.Proposed 2 comprehensibility measures considering semantics and structure of the tree. Classification trees are attractive for practical applications because of their comprehensibility. However, the literature on the parameters that influence their comprehensibility and usability is scarce. This paper systematically investigates how tree structure parameters (the number of leaves, branching factor, tree depth) and visualisation properties influence the tree comprehensibility. In addition, we analyse the influence of the question depth (the depth of the deepest leaf that is required when answering a question about a classification tree), which turns out to be the most important parameter, even though it is usually overlooked. The analysis is based on empirical data that is obtained using a carefully designed survey with 98 questions answered by 69 respondents. The paper evaluates several tree-comprehensibility metrics and proposes two new metrics (the weighted sum of the depths of leaves and the weighted sum of the branching factors on the paths from the root to the leaves) that are supported by the survey results. The main advantage of the new comprehensibility metrics is that they consider the semantics of the tree in addition to the tree structure itself.

Complex and differential glial responses in Alzheimer's disease and ageing.

Abstract: Glial cells and their association with neurones are fundamental for brain function. The emergence of complex neurone-glial networks assures rapid information transfer, creating a sophisticated circuitry where both types of neural cells work in concert, serving different activities. All glial cells, represented by astrocytes, oligodendrocytes, microglia and NG2-glia, are essential for brain homeostasis and defence. Thus, glia are key not only for normal central nervous system (CNS) function, but also to its dysfunction, being directly associated with all forms of neuropathological processes. Therefore, the progression and outcome of neurological and neurodegenerative diseases depend on glial reactions. In this review, we provide a concise account of recent data obtained from both human material and animal models demonstrating the pathological involvement of glia in neurodegenerative processes, including Alzheimer's disease (AD), as well as physiological ageing.