BET Inhibition-Induced GSK3β Feedback Enhances Lymphoma Vulnerability to PI3K Inhibitors

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase \u3b2 (GSK3\u3b2) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3\u3b2 S9 inhibitory phosphorylation, resulting in increased \u3b2-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3\u3b2 S9 phosphorylation levels and \u3b2-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3\u3b2 S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3\u3b2 regulation, providing a mechanistic rationale for combination strategies. In this study, Derenzini et al. demonstrate that BET inhibitors enhance lymphoma vulnerability to PI3K inhibitors by inducing GSK3\u3b2 feedback in a MYC-dependent manner and by downregulating E2-ubiquitin conjugating enzymes, which further enhance the feedback. These data provide the rationale for combining BET and PI3K inhibitors in lymphoma therapy

Production of (anti-)He-3 and (anti-)H-3 in p-Pb collisions at root s(NN)=5.02 TeV

The transverse momentum (p(T)) differential yields of (anti-)He-3 and (anti-)H-3 measured in p-Pb collisions at root s(NN) = 5.02 TeV with ALICE at the Large Hadron Collider (LHC) are presented. The ratios of the p(T)-integrated yields of (anti-)He-3 and (anti-)H-3 to the proton yields are reported, as well as the pT dependence of the coalescence parameters B-3 for (anti-)He-3 and (anti-)H-3. For (anti-)He-3, the results obtained in four classes of the mean charged-particle multiplicity density are also discussed. These results are compared to predictions from a canonical statistical hadronization model and coalescence approaches. An upper limit on the total yield of (4)(He) over bar is determined.Peer reviewe

Adaptation to climate change in Finland : Current state and future prospects

The KOKOSOPU project has aimed at a comprehensive evaluation of the national adaptation policy with particular emphasis on the National Adaptation Plan and international policy development. In addition, future challenges related to societal development have been taken into account. Projections of climate change, Finland’s Climate Act and the strengthened adaptation policy in the EU emphasise the importance of the national adaptation policy. A key objective of the National Adaptation Plan 2014–2022 was to strengthen the adaptive capacity of Finnish society. This objective is still relevant. The conditions for reaching the objective have, however, partly changed. First, cross border consequences of climate change are increasingly emphasised. Second, issues of justice and fairness with respect to the consequences of climate change and adaptation actions are being identified as central. Third, greater weight is given to the overall sustainability of adaptation and climate action. The changing conditions for climate change adaptation should be reflected in the allocation of resources, in improved coordination within the administration and in co-operation between the public and private sector. In addition, knowledge and education should be enhanced, and resources provided for RDI, and for monitoring and evaluation that supports continued improvement of adaptation activities

Adaptation to climate change in Finland : Current state and future prospects

The KOKOSOPU project has aimed at a comprehensive evaluation of the national adaptation policy with particular emphasis on the National Adaptation Plan and international policy development. In addition, future challenges related to societal development have been taken into account. Projections of climate change, Finland’s Climate Act and the strengthened adaptation policy in the EU emphasise the importance of the national adaptation policy. A key objective of the National Adaptation Plan 2014–2022 was to strengthen the adaptive capacity of Finnish society. This objective is still relevant. The conditions for reaching the objective have, however, partly changed. First, cross border consequences of climate change are increasingly emphasised. Second, issues of justice and fairness with respect to the consequences of climate change and adaptation actions are being identified as central. Third, greater weight is given to the overall sustainability of adaptation and climate action. The changing conditions for climate change adaptation should be reflected in the allocation of resources, in improved coordination within the administration and in co-operation between the public and private sector. In addition, knowledge and education should be enhanced, and resources provided for RDI, and for monitoring and evaluation that supports continued improvement of adaptation activities

Inclusive photon production at forward rapidities in proton-proton collisions at root s=0.9, 2.76 and 7 TeV

The multiplicity and pseudorapidity distributions of inclusive photons have been measured at forward rapidities (2.3 <eta <3.9) in proton-proton collisions at three center-of-mass energies, root s = 0.9, 2.76 and 7 TeV using the ALICE detector. It is observed that the increase in the average photon multiplicity as a function of beam energy is compatible with both a logarithmic and a power-law dependence. The relative increase in average photon multiplicity produced in inelastic pp collisions at 2.76 and 7 TeV center-of-mass energies with respect to 0.9 TeV are 37.2 +/- 0.3% (stat) +/- 8.8% (sys) and 61.2 +/- 0.3% (stat) +/- 7.6% (sys), respectively. The photon multiplicity distributions for all center-of-mass energies are well described by negative binomial distributions. The multiplicity distributions are also presented in terms of KNO variables. The results are compared to model predictions, which are found in general to underestimate the data at large photon multiplicities, in particular at the highest center-of-mass energy. Limiting fragmentation behavior of photons has been explored with the data, but is not observed in the measured pseudorapidity range.Peer reviewe

Aspects of bovine herpesvirus-1 infection in dairy and beef herds in the Republic of Ireland

<p>Abstract</p> <p>Background</p> <p>Infection with bovine herpesvirus-1 (BHV-1) causes a wide range of disease manifestations, including respiratory disease and abortion, with world-wide distribution. The primary objective of the present study was to describe aspects of BHV-1 infection and control on Irish farms, including herd-level seroprevalence (based on pooled sera) and vaccine usage.</p> <p>Methods</p> <p>The characteristics of a diagnostic indirect BHV-1 antibody ELISA test when used on serum pools were evaluated using laboratory replicates for use in the seroprevalence study. The output from this indirect ELISA was expressed as a percentage positivity (PP) value. A proposed cut off (PCO) PP was applied in a cross-sectional study of a stratified random sample of 1,175 Irish dairy and beef cattle herds in 2009, using serum pools, to estimate herd seroprevalence. The study was observational, based primarily on the analysis of existing samples, and only aggregated results were reported. For these reasons, ethical approval was not required. Bulk milk samples from a subset of 111 dairy herds were analysed using the same ELISA. Information regarding vaccine usage was determined in a telephone survey.</p> <p>Results</p> <p>A PCO PP of 7.88% was determined to give 97.1% sensitivity and 100% specificity relative to the use of the ELISA on individual sera giving maximization of the prevalence independent Youden's index, on receiver operating characteristics analysis of replicate results. The herd-level BHV-1 seroprevalence was 74.9% (95% CI - 69.9%-79.8%), with no significant difference between dairy and beef herds. 95.5% agreement in herd classification was found between bulk milk and serum pools. Only 1.8 percent of farmers used BHV-1 marker vaccine, 80% of which was live while 75% of vaccinated herds were dairy.</p> <p>A significant association was found between herd size (quartiles) and seroprevalence (quartiles).</p> <p>Conclusions</p> <p>The results from this study indicate BHV-1 infection is endemic, although BHV-1 vaccines are rarely used, in the cattle population in Ireland.</p

Multiplicity dependence of jet-like two-particle correlation structures in p-Pb collisions at root s(NN)=5.02 TeV

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 <p(T),(assoc) <p(T),(trig) <5.0 GeV/c is examined, to include correlations induced by jets originating from low momentum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range vertical bar eta vertical bar <0.9. The near-side long-range pseudorapidity correlations observed in high-multiplicity p-Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton-parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p-Pb collisions. Further, the number scales only in the intermediate multiplicity region with the number of binary nucleon-nucleon collisions estimated with a Glauber Monte-Carlo simulation. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).Peer reviewe

Multi-particle azimuthal correlations in p-Pb and Pb-Pb collisions at the CERN Large Hadron Collider

Measurements of multi-particle azimuthal correlations (cumulants) for charged particles in p-Pb and Pb-Pb collisions are presented. They help address the question of whether there is evidence for global, flow-like, azimuthal correlations in the p-Pb system. Comparisons are made to measurements from the larger Pb-Pb system, where such evidence is established. In particular, the second harmonic two-particle cumulants are found to decrease with multiplicity, characteristic of a dominance of few-particle correlations in p-Pb collisions. However, when a $|\Delta \eta|$ gap is placed to suppress such correlations, the two-particle cumulants begin to rise at high-multiplicity, indicating the presence of global azimuthal correlations. The Pb-Pb values are higher than the p-Pb values at similar multiplicities. In both systems, the second harmonic four-particle cumulants exhibit a transition from positive to negative values when the multiplicity increases. The negative values allow for a measurement of $v_{2}\{4\}$ to be made, which is found to be higher in Pb-Pb collisions at similar multiplicities. The second harmonic six-particle cumulants are also found to be higher in Pb-Pb collisions. In Pb-Pb collisions, we generally find $v_{2}\{4\} \simeq v_{2}\{6\}\neq 0$ which is indicative of a Bessel-Gaussian function for the $v_{2}$ distribution. For very high-multiplicity Pb-Pb collisions, we observe that the four- and six-particle cumulants become consistent with 0. Finally, third harmonic two-particle cumulants in p-Pb and Pb-Pb are measured. These are found to be similar for overlapping multiplicities, when a $|\Delta\eta| > 1.4$ gap is placed.Comment: 25 pages, 11 captioned figures, 3 tables, authors from page 20, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/87

Multiplicity dependence of jet-like two-particle correlations in p-Pb collisions at sNN\sqrt{s_{NN}} = 5.02 TeV

Two-particle angular correlations between unidentified charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV. The transverse-momentum range 0.7 $< p_{\rm{T}, assoc} < p_{\rm{T}, trig} <$ 5.0 GeV/$c$ is examined, to include correlations induced by jets originating from low momen\-tum-transfer scatterings (minijets). The correlations expressed as associated yield per trigger particle are obtained in the pseudorapidity range $|\eta|<0.9$. The near-side long-range pseudorapidity correlations observed in high-multiplicity p-Pb collisions are subtracted from both near-side short-range and away-side correlations in order to remove the non-jet-like components. The yields in the jet-like peaks are found to be invariant with event multiplicity with the exception of events with low multiplicity. This invariance is consistent with the particles being produced via the incoherent fragmentation of multiple parton--parton scatterings, while the yield related to the previously observed ridge structures is not jet-related. The number of uncorrelated sources of particle production is found to increase linearly with multiplicity, suggesting no saturation of the number of multi-parton interactions even in the highest multiplicity p-Pb collisions. Further, the number scales in the intermediate multiplicity region with the number of binary nucleon-nucleon collisions estimated with a Glauber Monte-Carlo simulation.Comment: 23 pages, 6 captioned figures, 1 table, authors from page 17, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/161

Dichomitus squalens partially tailors its molecular responses to the composition of solid wood

White-rot fungi, such as Dichomitus squalens, degrade all wood components and inhabit mixed-wood forests containing both soft- and hardwood species. In this study, we evaluated how D. squalens responded to the compositional differences in softwood [guaiacyl (G) lignin and higher mannan content] and hardwood [syringyl/guaiacyl (S/G) lignin and higher xylan content] using semi-natural solid cultures. Spruce (softwood) and birch (hardwood) sticks were degraded by D. squalens as measured by oxidation of the lignins using 2D-NMR. The fungal response as measured by transcriptomics, proteomics and enzyme activities showed a partial tailoring to wood composition. Mannanolytic transcripts and proteins were more abundant in spruce cultures, while a proportionally higher xylanolytic activity was detected in birch cultures. Both wood types induced manganese peroxidases to a much higher level than laccases, but higher transcript and protein levels of the manganese peroxidases were observed on the G-lignin rich spruce. Overall, the molecular responses demonstrated a stronger adaptation to the spruce rather than birch composition, possibly because D. squalens is mainly found degrading softwoods in nature, which supports the ability of the solid wood cultures to reflect the natural environment.Peer reviewe