Large variety in a panel of human colon cancer organoids in response to EZH2 inhibition

EZH2 inhibitors have gained great interest for their use as anti-cancer therapeutics. However, most research has focused on EZH2 mutant cancers and recently adverse effects of EZH2 inactivation have come to light. To determine whether colorectal cancer cells respond to EZH2 inhibition and to explore which factors influence the degree of response, we treated a panel of 20 organoid lines derived from human colon tumors with different concentrations of the EZH2 inhibitor GSK126. The resulting responses were associated with mutation status, gene expression and responses to other drugs. We found that the response to GSK126 treatment greatly varied between organoid lines. Response associated with the mutation status of ATRX and PAX2, and correlated with BIK expression. It also correlated well with response to Nutlin-3a which inhibits MDM2-p53 interaction thereby activating p53 signaling. Sensitivity to EZH2 ablation depended on the presence of wild type p53, as tumor organoids became resistant when p53 was mutated or knocked down. Our exploratory study provides insight into which genetic factors predict sensitivity to EZH2 inhibition. In addition, we show that the response to EZH2 inhibition requires wild type p53. We conclude that a subset of colorectal cancer patients may benefit from EZH2-targeting therapies

3D LES simulations of a static and vertically free-to-oscillate 4:1 rectangular cylinder: Effects of the grid resolution

Vortex induced vibration (VIV) is an important phenomenon which appears in flexible structures immersed in a moving fluid. This oscillation is self-sustained and self-limited, but VIV might cause fatigue damage and affect the structure's serviceability.In the present study, the aerodynamics of the flow fields around a static and vertically free-to-oscillate 4:1 rectangular cylinder are analysed by means of 3D LES simulations, adopting the OneEqEddy viscosity model. Integral parameters, pressure distributions, amplitudes of oscillation, coherences and correlations are obtained and compared with the available experimental data. Aiming to ascertain the impact of the boundary conditions and the grid resolution on the accuracy of results, five cases adopting 3 different meshes including two different spanwise discretisations have been considered. When studying the aerodynamics of the cylinder in static conditions, the influence of the spatial discretisation is very limited, and the agreement with experimental data is fairly good. On the other hand, for the free-to-oscillate cylinder, the structural response is dramatically dependent on the spanwise discretisation. The maximum amplitude of the structural response decreases as the mesh resolution increases, providing a closer fit with the experimental data. Also, the spanwise correlation of pressures is studied, finding remarkable differences depending on the level of spatial discretisation

Citizen science in environmental protection agencies

Citizen science, the active participation of the public in scientific research projects, is a rapidly expanding field in open science and open innovation. It provides an integrated model of public knowledge production and engagement with science. As a growing worldwide phenomenon, it is invigorated by evolving new technologies that connect people easily and effectively with the scientific community. Catalysed by citizens’ wishes to be actively involved in scientific processes, as a result of recent societal trends, it also offers contributions to the rise in tertiary education. In addition, citizen science provides a valuable tool for citizens to play a more active role in sustainable development. This book identifies and explains the role of citizen science within innovation in science and society, and as a vibrant and productive science-policy interface. The scope of this volume is global, geared towards identifying solutions and lessons to be applied across science, practice and policy. The chapters consider the role of citizen science in the context of the wider agenda of open science and open innovation, and discuss progress towards responsible research and innovation, two of the most critical aspects of science today

The Host Galaxies of X-ray Quasars Are Not Strong Star Formers

We use ultradeep SCUBA-2 850 μm observations (~0.37 mJy rms) of the 2 Ms Chandra Deep Field-North (CDF-N) and 4 Ms Chandra Deep Field-South X-ray fields to examine the amount of dusty star formation taking place in the host galaxies of high-redshift X-ray active galactic nuclei (AGNs). Supplementing with COSMOS, we measure the submillimeter fluxes of the 4–8 keV sources at $z\gt 1$, finding little flux at the highest X-ray luminosities but significant flux at intermediate luminosities. We determine graybody and MIR luminosities by fitting spectral energy distributions to each X-ray source and to each radio source in an ultradeep Karl G. Jansky Very Large Array (VLA) 1.4 GHz (11.5 μJy at $5\sigma$) image of the CDF-N. We confirm the far-infrared (FIR)-radio and mid-infrared (MIR)-radio correlations to z = 4 using the non-X-ray detected radio sources. Both correlations are also obeyed by the X-ray less luminous AGNs but not by the X-ray quasars. We interpret the low FIR luminosities relative to the MIR for the X-ray quasars as being due to a lack of star formation, while the MIR stays high due to the AGN contribution. We find that the FIR luminosity distributions are highly skewed and the means are dominated by a small number of high-luminosity galaxies. Thus, stacking or averaging analyses will overestimate the level of star formation taking place in the bulk of the X-ray sample. We conclude that most of the host galaxies of X-ray quasars are not strong star formers, perhaps because their star formation is suppressed by AGN feedback

Is there a maximum star formation rate in high-redshift galaxies?

We use the James Clerk Maxwell Telescope's SCUBA-2 camera to image a 400 arcmin2 area surrounding the GOODS-N field. The 850 μm rms noise ranges from a value of 0.49 mJy in the central region to 3.5 mJy at the outside edge. From these data, we construct an 850 μm source catalog to 2 mJy containing 49 sources detected above the 4σ level. We use an ultradeep (11.5 μJy at 5σ) 1.4 GHz image obtained with the Karl G. Jansky Very Large Array together with observations made with the Submillimeter Array to identify counterparts to the submillimeter galaxies. For most cases of multiple radio counterparts, we can identify the correct counterpart from new and existing Submillimeter Array data. We have spectroscopic redshifts for 62% of the radio sources in the 9' radius highest sensitivity region (556/894) and 67% of the radio sources in the GOODS-N region (367/543). We supplement these with a modest number of additional photometric redshifts in the GOODS-N region (30). We measure millimetric redshifts from the radio to submillimeter flux ratios for the unidentified submillimeter sample, assuming an Arp 220 spectral energy distribution. We find a radio-flux-dependent K – z relation for the radio sources, which we use to estimate redshifts for the remaining radio sources. We determine the star formation rates (SFRs) of the submillimeter sources based on their radio powers and their submillimeter fluxes and find that they agree well. The radio data are deep enough to detect star-forming galaxies with SFRs >2000 M ☉ yr–1 to z ~ 6. We find galaxies with SFRs up to ~6000 M ☉ yr–1 over the redshift range z = 1.5-6, but we see evidence for a turn-down in the SFR distribution function above 2000 M ☉ yr–1

PARP1 gene variation and microglial activity on [11C]PBR28 PET in older adults at risk for Alzheimer's disease

Increasing evidence suggests that inflammation is one pathophysio-logical mechanism in Alzheimer's disease (AD). Recent studies have identified an association between the poly (ADP-ribose) polymerase 1 (PARP1) gene and AD. This gene encodes a protein that is involved in many biological functions, including DNA repair and chromatin remodeling, and is a mediator of inflammation. Therefore, we performed a targeted genetic association analysis to investigate the relationship between the PARP1 polymorphisms and brain micro-glial activity as indexed by [11C]PBR28 positron emission tomography (PET). Participants were 26 non-Hispanic Caucasians in the Indiana Memory and Aging Study (IMAS). PET data were intensity-normalized by injected dose/total body weight. Average PBR standardized uptake values (SUV) from 6 bilateral regions of interest (thalamus, frontal, parietal, temporal, and cingulate cortices, and whole brain gray matter) were used as endophenotypes. Single nucleotide polymorphisms (SNPs) with 20% minor allele frequency that were within +/− 20 kb of the PARP1 gene were included in the analyses. Gene-level association analyses were performed using a dominant genetic model with translocator protein (18-kDa) (TSPO) genotype, age at PET scan, and gender as covariates. Analyses were performed with and without APOE ε4 status as a covariate. Associations with PBR SUVs from thalamus and cingulate were significant at corrected p<0.014 and <0.065, respectively. Subsequent multi-marker analysis with cingulate PBR SUV showed that individuals with the “C” allele at rs6677172 and “A” allele at rs61835377 had higher PBR SUV than individuals without these alleles (corrected P<0.03), and individuals with the “G” allele at rs6677172 and “G” allele at rs61835377 displayed the opposite trend (corrected P<0.065). A previous study with the same cohort showed an inverse relationship between PBR SUV and brain atrophy at a follow-up visit, suggesting possible protective effect of microglial activity against cortical atrophy. Interestingly, all 6 AD and 2 of 3 LMCI participants in the current analysis had one or more copies of the “GG” allele combination, associated with lower cingulate PBR SUV, suggesting that this gene variant warrants further investigation

Backward pion-nucleon scattering

A global analysis of the world data on differential cross sections and polarization asymmetries of backward pion-nucleon scattering for invariant collision energies above 3 GeV is performed in a Regge model. Including the $N_\alpha$, $N_\gamma$, $\Delta_\delta$ and $\Delta_\beta$ trajectories, we reproduce both angular distributions and polarization data for small values of the Mandelstam variable $u$, in contrast to previous analyses. The model amplitude is used to obtain evidence for baryon resonances with mass below 3 GeV. Our analysis suggests a $G_{39}$ resonance with a mass of 2.83 GeV as member of the $\Delta_{\beta}$ trajectory from the corresponding Chew-Frautschi plot.Comment: 12 pages, 16 figure