Showing papers by "Jagiellonian University published in 2016"

Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

Abstract: The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap ‘n’ Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.

Reinforcement Learning with Unsupervised Auxiliary Tasks

Abstract: Deep reinforcement learning agents have achieved state-of-the-art results by directly maximising cumulative reward. However, environments contain a much wider variety of possible training signals. In this paper, we introduce an agent that also maximises many other pseudo-reward functions simultaneously by reinforcement learning. All of these tasks share a common representation that, like unsupervised learning, continues to develop in the absence of extrinsic rewards. We also introduce a novel mechanism for focusing this representation upon extrinsic rewards, so that learning can rapidly adapt to the most relevant aspects of the actual task. Our agent significantly outperforms the previous state-of-the-art on Atari, averaging 880\% expert human performance, and a challenging suite of first-person, three-dimensional \emph{Labyrinth} tasks leading to a mean speedup in learning of 10$\times$ and averaging 87\% expert human performance on Labyrinth.

Designing the Business Models for Circular Economy—Towards the Conceptual Framework

Abstract: Switching from the current linear model of economy to a circular one has recently attracted increased attention from major global companies e.g., Google, Unilever, Renault, and policymakers attending the World Economic Forum. The reasons for this are the huge financial, social and environmental benefits. However, the global shift from one model of economy to another also concerns smaller companies on a micro-level. Thus, comprehensive knowledge on designing circular business models is needed to stimulate and foster implementation of the circular economy. Existing business models for the circular economy have limited transferability and there is no comprehensive framework supporting every kind of company in designing a circular business model. This study employs a literature review to identify and classify the circular economy characteristics according to a business model structure. The investigation in the eight sub-domains of research on circular business models was used to redefine the components of the business model canvas in the context of the circular economy. Two new components—the take-back system and adoption factors—have been identified, thereby leading to the conceptualization of an extended framework for the circular business model canvas. Additionally, the triple fit challenge has been recognized as an enabler of the transition towards a circular business model. Some directions for further research have been outlined, as well.

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial

Abstract: Importance Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. Objective To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. Design, Setting, and Participants The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Interventions Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. Main Outcomes and Measures The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, −56.5 mg/dL [95% CI, −59.7 to −53.4]; P P 3 with placebo and 5.8 mm 3 with evolocumab (difference, −4.9 mm 3 [95% CI, −7.3 to −2.5]; P P P Conclusions and Relevance Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. Trial Registration clinicaltrials.gov Identifier:NCT01813422

Editing DNA Methylation in the Mammalian Genome

Abstract: Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.

Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study

Abstract: Summary Background Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. Methods In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4–5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Findings Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1–14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5–86·6) of 107 patients. The most common grade 3–4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related). Interpretation Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia. Funding AbbVie and Genentech.

Non-bee insects are important contributors to global crop pollination

Abstract: Wild and managed bees are well documented as effective pollinators of global crops of economic importance. However, the contributions by pollinators other than bees have been little explored despite their potential to contribute to crop production and stability in the face of environmental change. Non-bee pollinators include flies, beetles, moths, butterflies, wasps, ants, birds, and bats, among others. Here we focus on non-bee insects and synthesize 39 field studies from five continents that directly measured the crop pollination services provided by non-bees, honey bees, and other bees to compare the relative contributions of these taxa. Non-bees performed 25–50% of the total number of flower visits. Although non-bees were less effective pollinators than bees per flower visit, they made more visits; thus these two factors compensated for each other, resulting in pollination services rendered by non-bees that were similar to those provided by bees. In the subset of studies that measured fruit set, fruit set increased with non-bee insect visits independently of bee visitation rates, indicating that non-bee insects provide a unique benefit that is not provided by bees. We also show that non-bee insects are not as reliant as bees on the presence of remnant natural or seminatural habitat in the surrounding landscape. These results strongly suggest that non-bee insect pollinators play a significant role in global crop production and respond differently than bees to landscape structure, probably making their crop pollination services more robust to changes in land use. Non-bee insects provide a valuable service and provide potential insurance against bee population declines.

The quiescent intracluster medium in the core of the Perseus cluster

Abstract: The Hitomi collaboration reports X-ray observations of the core of the Perseus cluster of galaxies the brightest X-ray-emitting cluster in the sky. Such clusters typically consist of tens to thousands of galaxies bound together by gravity and are studied as models of both small-scale cosmology and large-scale astrophysical processes. The data reveal a remarkably quiescent atmosphere, where gas velocities are quite low, with a line-of-sight velocity dispersion of about 164 kilometres per second at a distance of 3060 kiloparsecs from the central nucleus.

Muon reconstruction performance of the ATLAS detector in proton–proton collision data at √ s =13 TeV

Abstract: This article documents the performance of the ATLAS muon identification and reconstruction using the first LHC dataset recorded at s√ = 13 TeV in 2015. Using a large sample of J/ψ→μμ and Z→μμ decays from 3.2 fb−1 of pp collision data, measurements of the reconstruction efficiency, as well as of the momentum scale and resolution, are presented and compared to Monte Carlo simulations. The reconstruction efficiency is measured to be close to 99% over most of the covered phase space (|η| 2.2, the pT resolution for muons from Z→μμ decays is 2.9% while the precision of the momentum scale for low-pT muons from J/ψ→μμ decays is about 0.2%.

Acceleration of petaelectronvolt protons in the Galactic Centre

Abstract: Galactic cosmic rays reach energies of at least a few petaelectronvolts(1) (of the order of 1015 electronvolts). This implies that our Galaxy contains petaelectronvolt accelerators ('PeVatrons'), b ...

Performance of $b$-Jet Identification in the ATLAS Experiment

Abstract: The identification of jets containing b hadrons is important for the physics programme of the ATLAS experiment at the Large Hadron Collider. Several algorithms to identify jets containing b hadrons are described, ranging from those based on the reconstruction of an inclusive secondary vertex or the presence of tracks with large impact parameters to combined tagging algorithms making use of multi-variate discriminants. An independent b-tagging algorithm based on the reconstruction of muons inside jets as well as the b-tagging algorithm used in the online trigger are also presented. The b-jet tagging efficiency, the c-jet tagging efficiency and the mistag rate for light flavour jets in data have been measured with a number of complementary methods. The calibration results are presented as scale factors defined as the ratio of the efficiency (or mistag rate) in data to that in simulation. In the case of b jets, where more than one calibration method exists, the results from the various analyses have been combined taking into account the statistical correlation as well as the correlation of the sources of systematic uncertainty.

Performance of pile-up mitigation techniques for jets in pp collisions at √s = 8 TeV using the ATLAS detector

Abstract: The large rate of multiple simultaneous protonproton interactions, or pile-up, generated by the Large Hadron Collider in Run 1 required the development of many new techniques to mitigate the advers ...

Luminosity determination in pp collisions at √s = 8 TeV using the ATLAS detector at the LHC

Abstract: The luminosity determination for the ATLAS detector at the LHC during pp collisions at s√= 8 TeV in 2012 is presented. The evaluation of the luminosity scale is performed using several luminometers ...

Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1)

Abstract: Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.

Observation of Long-Range Elliptic Azimuthal Anisotropies in s =13 and 2.76 TeV pp Collisions with the ATLAS Detector

Abstract: ATLAS has measured two-particle correlations as a function of relative azimuthal-angle, $\Delta \phi$, and pseudorapidity, $\Delta \eta$, in $\sqrt{s}$=13 and 2.76 TeV $pp$ collisions at the LHC using charged particles measured in the pseudorapidity interval $|\eta|$<2.5. The correlation functions evaluated in different intervals of measured charged-particle multiplicity show a multiplicity-dependent enhancement at $\Delta \phi \sim 0$ that extends over a wide range of $\Delta\eta$, which has been referred to as the "ridge". Per-trigger-particle yields, $Y(\Delta \phi)$, are measured over 2<$|\Delta\eta|$<5. For both collision energies, the $Y(\Delta \phi)$ distribution in all multiplicity intervals is found to be consistent with a linear combination of the per-trigger-particle yields measured in collisions with less than 20 reconstructed tracks, and a constant combinatoric contribution modulated by $\cos{(2\Delta \phi)}$. The fitted Fourier coefficient, $v_{2,2}$, exhibits factorization, suggesting that the ridge results from per-event $\cos{(2\phi)}$ modulation of the single-particle distribution with Fourier coefficients $v_2$. The $v_2$ values are presented as a function of multiplicity and transverse momentum. They are found to be approximately constant as a function of multiplicity and to have a $p_{\mathrm{T}}$ dependence similar to that measured in $p$+Pb and Pb+Pb collisions. The $v_2$ values in the 13 and 2.76 TeV data are consistent within uncertainties. These results suggest that the ridge in $pp$ collisions arises from the same or similar underlying physics as observed in $p$+Pb collisions, and that the dynamics responsible for the ridge has no strong $\sqrt{s}$ dependence.

Search for an additional, heavy Higgs boson in the H → ZZ decay channel at √s = 8 TeV in pp collision data with the ATLAS detector

Abstract: A search is presented for a high-mass Higgs boson in the , , , and decay modes using the ATLAS detector at the CERN Large Hadron Collider. The search uses proton-proton collision data at a centre-of-mass energy of 8 TeV corresponding to an integrated luminosity of 20.3 fb. The results of the search are interpreted in the scenario of a heavy Higgs boson with a width that is small compared with the experimental mass resolution. The Higgs boson mass range considered extends up to for all four decay modes and down to as low as 140 , depending on the decay mode. No significant excess of events over the Standard Model prediction is found. A simultaneous fit to the four decay modes yields upper limits on the production cross-section of a heavy Higgs boson times the branching ratio to boson pairs. 95 % confidence level upper limits range from 0.53 pb at GeV to 0.008 pb at GeV for the gluon-fusion production mode and from 0.31 pb at GeV to 0.009 pb at GeV for the vector-boson-fusion production mode. The results are also interpreted in the context of Type-I and Type-II two-Higgs-doublet models.

MINUTE-TIMESCALE >100 MeV γ-RAY VARIABILITY during the GIANT OUTBURST of QUASAR 3C 279 OBSERVED by FERMI-LAT in 2015 June

Abstract: On 2015 June 16, Fermi-LAT observed a giant outburst from the flat spectrum radio quasar 3C 279 with a peak $>100$ MeV flux of $\sim3.6\times10^{-5}\;{\rm photons}\;{\rm cm}^{-2}\;{\rm s}^{-1}$ averaged over orbital period intervals. It is the historically highest $\gamma$-ray flux observed from the source including past EGRET observations, with the $\gamma$-ray isotropic luminosity reaching $\sim10^{49}\;{\rm erg}\;{\rm s}^{-1}$. During the outburst, the Fermi spacecraft, which has an orbital period of 95.4 min, was operated in a special pointing mode to optimize the exposure for 3C 279. For the first time, significant flux variability at sub-orbital timescales was found in blazar observations by Fermi-LAT. The source flux variability was resolved down to 2-min binned timescales, with flux doubling times less than 5 min. The observed minute-scale variability suggests a very compact emission region at hundreds of Schwarzschild radii from the central engine in conical jet models. A minimum bulk jet Lorentz factor ($\Gamma$) of 35 is necessary to avoid both internal $\gamma$-ray absorption and super-Eddington jet power. In the standard external-radiation-Comptonization scenario, $\Gamma$ should be at least 50 to avoid overproducing the synchrotron-self-Compton component. However, this predicts extremely low magnetization ($\sim5\times10^{-4}$). Equipartition requires $\Gamma$ as high as 120, unless the emitting region is a small fraction of the dissipation region. Alternatively, we consider $\gamma$ rays originating as synchrotron radiation of $\gamma_{\rm e}\sim1.6\times10^6$ electrons, in magnetic field $B\sim1.3$ kG, accelerated by strong electric fields $E\sim B$ in the process of magnetoluminescence. At such short distance scales, one cannot immediately exclude production of $\gamma$ rays in hadronic processes.

TGF-β1/Smads and miR-21 in Renal Fibrosis and Inflammation

Abstract: Renal fibrosis, irrespective of its etiology, is a final common stage of almost all chronic kidney diseases. Increased apoptosis, epithelial-to-mesenchymal transition, and inflammatory cell infiltration characterize the injured kidney. On the molecular level, transforming growth factor-β1 (TGF-β1)-Smad3 signaling pathway plays a central role in fibrotic kidney disease. Recent findings indicate the prominent role of microRNAs, small noncoding RNA molecules that inhibit gene expression through the posttranscriptional repression of their target mRNAs, in different pathologic conditions, including renal pathophysiology. miR-21 was also shown to play a dynamic role in inflammatory responses and in accelerating injury responses to promote organ failure and fibrosis. Understanding the cellular and molecular bases of miR-21 involvement in the pathogenesis of kidney diseases, including inflammatory reaction, could be crucial for their early diagnosis. Moreover, the possibility of influencing miR-21 level by specific antagomirs may be considered as an approach for treatment of renal diseases.

Variable chlorophyll fluorescence and its use for assessing physiological condition of plant photosynthetic apparatus

Abstract: Analysis of plant behavior under diverse environmental conditions would be impossible without the methods for adequate assessment of the processes occurring in plants. The photosynthetic apparatus and its reaction to stress factors provide a reliable source of information on plant condition. One of the most informative methods based on monitoring the plant biophysical characteristics consists in detection and analysis of chlorophyll a fluorescence. Fluorescence is mainly emitted by chlorophyll a from the antenna complexes of photosystem II (PSII). However, fluorescence depends not only on the processes in the pigment matrix or PSII reaction centers but also on the redox reactions at the PSII donor and acceptor sides and even in the entire electron transport chain. Presently, a large variety of fluorometers from various manufacturers are available. Although application of such fluorometers does not require specialized training, the correct interpretation of the results would need sufficient knowledge for converting the instrumental data into the information on the condition of analyzed plants. This review is intended for a wide range of specialists employing fluorescence techniques for monitoring the physiological plant condition. It describes in a comprehensible way the theoretical basis of light emission by chlorophyll molecules, the origin of variable fluorescence, as well as relations between the fluorescence parameters, the redox state of electron carriers, and the light reactions of photosynthesis. Approaches to processing and analyzing the fluorescence induction curves are considered in detail on the basis of energy flux theory in the photosynthetic apparatus developed by Prof. Reto J. Strasser and known as a “JIP-test.” The physical meaning and relation of each calculated parameter to certain photosynthetic characteristics are presented, and examples of using these parameters for the assessment of plant physiological condition are outlined.