Showing papers by "University of Ljubljana published in 2011"

Characterizing the RNA targets and position-dependent splicing regulation by TDP-43

Abstract: TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. In addition, we identified unusually long clusters of TDP-43 binding at deep intronic positions downstream of silenced exons. A substantial proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or have been implicated in neurological diseases, highlighting the importance of TDP-43 for the regulation of splicing in the brain.

Uniformity of rotavirus strain nomenclature proposed by the Rotavirus Classification Working Group (RCWG).

Abstract: In April 2008, a nucleotide-sequence-based, complete genome classification system was developed for group A rotaviruses (RVs). This system assigns a specific genotype to each of the 11 genome segments of a particular RV strain according to established nucleotide percent cutoff values. Using this approach, the genome of individual RV strains are given the complete descriptor of Gx-P[x]-Ix-Rx-Cx-Mx-Ax-Nx-Tx-Ex-Hx. The Rotavirus Classification Working Group (RCWG) was formed by scientists in the field to maintain, evaluate and develop the RV genotype classification system, in particular to aid in the designation of new genotypes. Since its conception, the group has ratified 51 new genotypes: as of April 2011, new genotypes for VP7 (G20-G27), VP4 (P[28]-P[35]), VP6 (I12-I16), VP1 (R5-R9), VP2 (C6-C9), VP3 (M7-M8), NSP1 (A15-A16), NSP2 (N6-N9), NSP3 (T8-T12), NSP4 (E12-E14) and NSP5/6 (H7-H11) have been defined for RV strains recovered from humans, cows, pigs, horses, mice, South American camelids (guanaco), chickens, turkeys, pheasants, bats and a sugar glider. With increasing numbers of complete RV genome sequences becoming available, a standardized RV strain nomenclature system is needed, and the RCWG proposes that individual RV strains are named as follows: RV group/species of origin/country of identification/common name/year of identification/G- and P-type. In collaboration with the National Center for Biotechnology Information (NCBI), the RCWG is also working on developing a RV-specific resource for the deposition of nucleotide sequences. This resource will provide useful information regarding RV strains, including, but not limited to, the individual gene genotypes and epidemiological and clinical information. Together, the proposed nomenclature system and the NCBI RV resource will offer highly useful tools for investigators to search for, retrieve, and analyze the ever-growing volume of RV genomic data.

Mechanism of Endosomal TLR Inhibition by Antimalarial Drugs and Imidazoquinolines

Abstract: Endosomal TLRs play an important role in innate immune response as well as in autoimmune processes. In the therapy of systemic lupus erythematosus, antimalarial drugs chloroquine, hydroxychloroquine, and quinacrine have been used for a long time. Their suppression of endosomal TLR activation has been attributed to the inhibition of endosomal acidification, which is a prerequisite for the activation of these receptors. We discovered that chloroquine inhibits only activation of endosomal TLRs by nucleic acids, whereas it augments activation of TLR8 by a small synthetic compound, R848. We detected direct binding of antimalarials to nucleic acids by spectroscopic experiments and determined their cellular colocalization. Further analysis revealed that other nucleic acid-binding compounds, such as propidium iodide, also inhibited activation of endosomal TLRs and colocalized with nucleic acids to endosomes. We found that imidazoquinolines, which are TLR7/8 agonists, inhibit TLR9 and TLR3 even in the absence of TLR7 or TLR8, and their mechanism of inhibition is similar to the antimalarials. In contrast to bafilomycin, none of the tested antimalarials and imidazoquinolines inhibited endosomal proteolysis or increased the endosomal pH, confirming that inhibition of pH acidification is not the underlying cause of inhibition. We conclude that the direct binding of inhibitors to nucleic acids mask their TLR-binding epitope and may explain the efficiency of those compounds in the treatment of autoimmune diseases.

Charged-particle multiplicities in pp interactions measured with the ATLAS detector at the LHC

Abstract: Measurements are presented from proton-proton collisions at centre-of-mass energies of root s = 0.9, 2.36 and 7 TeV recorded with the ATLAS detector at the LHC. Events were collected using a single-arm minimum-bias trigger. The charged-particle multiplicity, its dependence on transverse momentum and pseudorapidity and the relationship between the mean transverse momentum and charged-particle multiplicity are measured. Measurements in different regions of phase space are shown, providing diffraction-reduced measurements as well as more inclusive ones. The observed distributions are corrected to well-defined phase-space regions, using model-independent corrections. The results are compared to each other and to various Monte Carlo (MC) models, including a new AMBT1 pythia6 tune. In all the kinematic regions considered, the particle multiplicities are higher than predicted by the MC models. The central charged-particle multiplicity per event and unit of pseudorapidity, for tracks with p(T) > 100 MeV, is measured to be 3.483 +/- 0.009 (stat) +/- 0.106 (syst) at root s = 0.9 TeV and 5.630 +/- 0.003 (stat) +/- 0.169 (syst) at root s = 7 TeV.

Effect of Continuous Glucose Monitoring on Hypoglycemia in Type 1 Diabetes

Abstract: OBJECTIVE To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A 1c (HbA 1c ) RESULTS The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA 1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference −0.27%; 95% CI −0.47 to −0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009). CONCLUSIONS Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA 1c in children and adults with type 1 diabetes.

Open XXZ spin chain: nonequilibrium steady state and a strict bound on ballistic transport.

Abstract: An explicit matrix product ansatz is presented, in the first two orders in the (weak) coupling parameter, for the nonequilibrium steady state of the homogeneous, nearest neighbor Heisenberg XXZ spin 1/2 chain driven by Lindblad operators which act only at the edges of the chain The first order of the density operator becomes, in the thermodynamic limit, an exact pseudolocal conservation law and yields-via the Mazur inequality-a rigorous lower bound on the high-temperature spin Drude weight Such a Mazur bound is a nonvanishing fractal function of the anisotropy parameter Δ for |Δ|<1

Statistical tests for power-law cross-correlated processes

Abstract: For stationary time series, the cross-covariance and the cross-correlation as functions of time lag $n$ serve to quantify the similarity of two time series. The latter measure is also used to assess whether the cross-correlations are statistically significant. For nonstationary time series, the analogous measures are detrended cross-correlations analysis (DCCA) and the recently proposed detrended cross-correlation coefficient, ${\ensuremath{\rho}}_{\mathrm{DCCA}}(T,n)$, where $T$ is the total length of the time series and $n$ the window size. For ${\ensuremath{\rho}}_{\mathrm{DCCA}}(T,n)$, we numerically calculated the Cauchy inequality $\ensuremath{-}1\ensuremath{\le}{\ensuremath{\rho}}_{\mathrm{DCCA}}(T,n)\ensuremath{\le}1$. Here we derive $\ensuremath{-}1\ensuremath{\le}{\ensuremath{\rho}}_{\mathrm{DCCA}}(T,n)\ensuremath{\le}1$ for a standard variance-covariance approach and for a detrending approach. For overlapping windows, we find the range of ${\ensuremath{\rho}}_{\mathrm{DCCA}}$ within which the cross-correlations become statistically significant. For overlapping windows we numerically determine---and for nonoverlapping windows we derive---that the standard deviation of ${\ensuremath{\rho}}_{\mathrm{DCCA}}(T,n)$ tends with increasing $T$ to $1/T$. Using ${\ensuremath{\rho}}_{\mathrm{DCCA}}(T,n)$ we show that the Chinese financial market's tendency to follow the U.S. market is extremely weak. We also propose an additional statistical test that can be used to quantify the existence of cross-correlations between two power-law correlated time series.

EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjögren's syndrome

Abstract: Objectives To develop a score for assessment of patients9 symptoms in primary Sjogren9s syndrome (SS): the EULAR SS Patient Reported Index (ESSPRI). Methods Dryness, pain, somatic and mental fatigue were identified as the main symptoms of patients with primary SS, in studies developing the Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptoms Inventory (SSI). It was suspected that a single 0–10 numerical scale for each domain was sufficient to assess these symptoms. These four scales were gathered to form the ESSPRI. 230 patients, from 12 countries completed the ESSPRI, SSI and PROFAD questionnaires and a 0–10 patient global assessment (PGA). Correlations between each symptom and PGA were obtained. Multiple regression modelling, using PGA as ‘gold standard’ was used to select domains and estimate their weights. Results PGA had good correlation with dryness, limb pain, fatigue and mental fatigue (r=0.49–0.59, all p Conclusion ESSPRI is a very simple index designed to measure patients9 symptoms in primary SS. It has good construct validity and is well correlated with SSI and PROFAD. ESSPRI should now be validated for use as an outcome measure in clinical trials.

Reconfigurable Knots and Links in Chiral Nematic Colloids

Abstract: Tying knots and linking microscopic loops of polymers, macromolecules, or defect lines in complex materials is a challenging task for material scientists We demonstrate the knotting of microscopic topological defect lines in chiral nematic liquid-crystal colloids into knots and links of arbitrary complexity by using laser tweezers as a micromanipulation tool All knots and links with up to six crossings, including the Hopf link, the Star of David, and the Borromean rings, are demonstrated, stabilizing colloidal particles into an unusual soft matter The knots in chiral nematic colloids are classified by the quantized self-linking number, a direct measure of the geometric, or Berry’s, phase Forming arbitrary microscopic knots and links in chiral nematic colloids is a demonstration of how relevant the topology can be for the material engineering of soft matter

Autochthonous dengue fever in Croatia, August-September 2010.

Abstract: After information about a dengue case in Germany acquired in Croatia, health professionals and the public in Croatia were alerted to assess the situation and to enhance mosquito control, resulting in the diagnosis of a second case of autochthonous dengue fever in the same area and the detection of 15 persons with evidence of recent dengue infection. Mosquito control measures were introduced. The circumstances of dengue virus introduction to Croatia remain unresolved.

Preliminary criteria for the very early diagnosis of systemic sclerosis: results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group

Abstract: Objective: To identify a core set of preliminary items considered as important for the very early diagnosis of systemic sclerosis (SSc). Methods: A list of items provided by European League Against Rheumatism (EULAR) Scleroderma Trial and Research(EUSTAR) centres were subjected to a Delphi exercise among 110 experts in the field of SSc. In round 1, experts were asked to choose the items they considered as the most important for the very early diagnosis of SSc. In round 2, experts were asked to reconsider the items accepted after the first stage. In round 3, the clinical relevance of selected items and their importance as measures that would lead to an early referral process were rated using appropriateness scores. Results: Physicians from 85 EUSTAR centres participated in the study and provided an initial list of 121 items. After three Delphi rounds, the steering committee, with input from external experts, collapsed the 121 items into three domains containing seven items, developed as follows: skin domain (puffy fingers/puffy swollen digits turning into sclerodactily);vascular domain (Raynaud's phenomenon, abnormal capillaroscopy with scleroderma pattern) and laboratory domain (antinuclear, anticentromere and antitopoisomerase-I antibodies). Finally, the whole assembly of EUSTAR centres ratified with a majority vote the results in a final face-to-face meeting. Conclusion: The three Delphi rounds allowed us to identify the items considered by experts as necessary for the very early diagnosis of SSc. The validation of these items to establish diagnostic criteria is currently ongoing in a prospective observational cohort.

New Abundant Microbial Groups in Aquatic Hypersaline Environments

Abstract: We describe the microbiota of two hypersaline saltern ponds, one of intermediate salinity (19%) and a NaCl saturated crystallizer pond (37%) using pyrosequencing. The analyses of these metagenomes (nearly 784 Mb) reaffirmed the vast dominance of Haloquadratum walsbyi but also revealed novel, abundant and previously unsuspected microbial groups. We describe for the first time, a group of low GC Actinobacteria, related to freshwater Actinobacteria, abundant in low and intermediate salinities. Metagenomic assembly revealed three new abundant microbes: a low-GC euryarchaeon with the lowest GC content described for any euryarchaeon, a high-GC euryarchaeon and a gammaproteobacterium related to Alkalilimnicola and Nitrococcus. Multiple displacement amplification and sequencing of the genome from a single archaeal cell of the new low GC euryarchaeon suggest a photoheterotrophic and polysaccharide-degrading lifestyle and its relatedness to the recently described lineage of Nanohaloarchaea. These discoveries reveal the combined power of an unbiased metagenomic and single cell genomic approach.

Fast algorithms for determining (generalized) core groups in social networks

Abstract: The structure of a large network (graph) can often be revealed by partitioning it into smaller and possibly more dense sub-networks that are easier to handle. One of such decompositions is based on "k-cores", proposed in 1983 by Seidman. Together with connectivity components, cores are one among few concepts that provide efficient decompositions of large graphs and networks. In this paper we propose an efficient algorithm for determining the cores decomposition of a given network with complexity $${\mathcal{O}(m)}$$ , where m is the number of lines (edges or arcs). In the second part of the paper the classical concept of k-core is generalized in a way that uses a vertex property function instead of degree of a vertex. For local monotone vertex property functions the corresponding generalized cores can be determined in $${\mathcal{O}(m\cdot\max(\Delta,\log{n}))}$$ time, where n is the number of vertices and Δ is the maximum degree. Finally the proposed algorithms are illustrated by the analysis of a collaboration network in the field of computational geometry.

Characterization and intercomparison of aerosol absorption photometers: result of two intercomparison workshops

Abstract: . Absorption photometers for real time application have been available since the 1980s, but the use of filter-based instruments to derive information on aerosol properties (absorption coefficient and black carbon, BC) is still a matter of debate. Several workshops have been conducted to investigate the performance of individual instruments over the intervening years. Two workshops with large sets of aerosol absorption photometers were conducted in 2005 and 2007. The data from these instruments were corrected using existing methods before further analysis. The inter-comparison shows a large variation between the responses to absorbing aerosol particles for different types of instruments. The unit to unit variability between instruments can be up to 30% for Particle Soot Absorption Photometers (PSAPs) and Aethalometers. Multi Angle Absorption Photometers (MAAPs) showed a variability of less than 5%. Reasons for the high variability were identified to be variations in sample flow and spot size. It was observed that different flow rates influence system performance with respect to response to absorption and instrumental noise. Measurements with non absorbing particles showed that the current corrections of a cross sensitivity to particle scattering are not sufficient. Remaining cross sensitivities were found to be a function of the total particle load on the filter. The large variation between the response to absorbing aerosol particles for different types of instruments indicates that current correction functions for absorption photometers are not adequate.

Luminosity Determination in pp Collisions at sqrt(s)=7 TeV Using the ATLAS Detector at the LHC

Abstract: Measurements of luminosity obtained using the ATLAS detector during early running of the Large Hadron Collider (LHC) at root s = 7 TeV are presented. The luminosity is independently determined using several detectors and multiple algorithms, each having different acceptances, systematic uncertainties and sensitivity to background. The ratios of the luminosities obtained from these methods are monitored as a function of time and of mu, the average number of inelastic interactions per bunch crossing. Residual time- and mu-dependence between the methods is less than 2% for 0 < mu < 2.5. Absolute luminosity calibrations, performed using beam separation scans, have a common systematic uncertainty of +/- 11%, dominated by the measurement of the LHC beam currents. After calibration, the luminosities obtained from the different methods differ by at most +/- 2%. The visible cross sections measured using the beam scans are compared to predictions obtained with the PYTHIA and PHOJET event generators and the ATLAS detector simulation.

Exact nonequilibrium steady state of a strongly driven open XXZ chain.

Abstract: An exact and explicit ladder-tensor-network ansatz is presented for the nonequilibrium steady state of an anisotropic Heisenberg $XXZ$ spin-$1/2$ chain which is driven far from equilibrium with a pair of Lindblad operators acting on the edges of the chain only. We show that the steady-state density operator of a finite system of size $n$ is---apart from a normalization constant---a polynomial of degree $2n\ensuremath{-}2$ in the coupling constant. Efficient computation of physical observables is facilitated in terms of a transfer operator reminiscent of a classical Markov process. In the isotropic case we find cosine spin profiles, $1/{n}^{2}$ scaling of the spin current, and long-range correlations in the steady state. This is a fully nonperturbative extension of a recent result [Phys. Rev. Lett. 106, 217206 (2011)].

Rotavirus genotypes co-circulating in Europe between 2006 and 2009 as determined by EuroRotaNet, a pan-European collaborative strain surveillance network

Abstract: EuroRotaNet, a laboratory network, was established in order to determine the diversity of co-circulating rotavirus strains in Europe over three or more rotavirus seasons from 2006/2007 and currently includes 16 countries. This report highlights the tremendous diversity of rotavirus strains co-circulating in the European population during three years of surveillance since 2006/2007 and points to the possible origins of these strains including genetic reassortment and interspecies transmission. Furthermore, the ability of the network to identify strains circulating with an incidence of ≥1% allowed the identification of possible emerging strains such as G8 and G12 since the beginning of the study; analysis of recent data indicates their increased incidence. The introduction of universal rotavirus vaccination in at least two of the participating countries, and partial vaccine coverage in some others may provide data on diversity driven by vaccine introduction and possible strain replacement in Europe.

Oxidative stress in schizophrenia.

Abstract: Increasing evidence indicates that oxidative damage exists in schizophrenia. Available literature about possible mechanisms of oxidative stress induction was reviewed. Furthermore, possibilities of measuring biomarkers of schizophrenia outside the central nervous system compartment, their specificity for different types of schizophrenia and potential therapeutic strategies to prevent oxidative injuries in schizophrenia were discussed. Data were extracted from published literature found in Medline, Embase, Biosis, Cochrane and Web of Science, together with hand search of references. Search terms were: schizophrenia, oxidative stress, antipsychotics, antioxidants and fatty acids. Finding a sensitive, specific and non invasive biomarker of schizophrenia, which could be measured in peripheral tissue, still stays an important task. Antioxidant enzymes, markers of lipid peroxidation, oxidatively modified proteins and DNA are most commonly used. As it considers the supplemental therapy, according to our meta-analysis vitamin E could potentially improve tardive dyskinesia, while for the effect of therapy with polyunsaturated fatty acids there is no clear evidence. Oxidative stress is a part of the pathology in schizophrenia and appears as a promising field to develop new therapeutic strategies. There is a need for well designed, placebo controlled trials with supplementation therapy in schizophrenia.

Condensed DNA: condensing the concepts.

Abstract: DNA is stored in vivo in a highly compact, so-called condensed phase, where gene regulatory processes are governed by the intricate interplay between different states of DNA compaction. These systems often have surprising properties, which one would not predict from classical concepts of dilute solutions. The mechanistic details of DNA packing are essential for its functioning, as revealed by the recent developments coming from biochemistry, electrostatics, statistical mechanics, and molecular and cell biology. Different aspects of condensed DNA behavior are linked to each other, but the links are often hidden in the bulk of experimental and theoretical details. Here we try to condense some of these concepts and provide interconnections between the different fields. After a brief description of main experimental features of DNA condensation inside viruses, bacteria, eukaryotes and the test tube, main theoretical approaches for the description of these systems are presented. We end up with an extended discussion of the role of DNA condensation in the context of gene regulation and mention potential applications of DNA condensation in gene therapy and biotechnology.

Analysis of alternative splicing associated with aging and neurodegeneration in the human brain

Abstract: Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)-dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)-dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration.

Rethinking energy efficiency models of cellular networks with embodied energy

Abstract: The continuous increase in energy consumption by cellular networks requires rethinking their energy efficiency. Current research indicates that one third of operating energy could be saved by reducing the transmission power of base stations. However, this approach requires the introduction of a range of additional equipment containing more embodied energy - consumed by all processes associated with the production of equipment. This problem is addressed first in this article. Furthermore, a new cellular network energy efficiency model with embodied energy is proposed, and optimization between the number of cells and their coverage is investigated. Contrary to previous works, we have found that embodied energy accounts for a significant proportion of total energy consumption and cannot be neglected. The simulation results confirm an important trade-off between operating and embodied energies, which can provide some practical guidelines for designing energy-efficient cellular access networks. The new model considering embodied energy is not limited to just cellular networks, but to other telecommunications, such as wireless local area networks and wired networks.