Rubidazone vs adriamycin: an evaluation of their differential toxicity in the spleen colony assay system.

Rubidazone, the new semi-synthetic benzol hydrazone hydrochloride derivative of dauorubicin, has proved on a molecular weight basis to be less toxic than adriamycin and similar to daunorubicin in cardiac toxicity studies in the hamster as well as in other in vivo and in vitro test systems. It has proven effectiveness against several animal tumours and human acute leukaemias. We have compared the inhibitory effect of rubidazone to that of adriamycin on P388 leukaemia and normal bone marrow colony-forming units (CFU) using the spleen colony assay system in male DBA2 mice. The efficacy ratios (i.e., the ratio of the slopes of the normal bone marrow CFU to leukaemic CFU dose-survival curves) in the spleen colony assay system for rubidazone and adriamycin were 7-8 and 7-5 respectively. This near identity of efficacy ratios fro rubidazone and adriamycin correlated with the results of median survival time studies in the leukaemic mice. Their dose-median survival time curves were almost parallel, having nearly identical slopes. Rubidazone's equal therapeutic index as compared to adriamycin in the spleen colony assay system together with its known decreased toxicity to cardiac muscle cells makes it an extremely promising new anthracycline derivative to study in comparison to adriamycin in human malignancies

Study of fundamental rights limitations for online enforcement through self-regulation

Effective Protection of Fundamental Rights in a pluralist worl

Inferring the dark matter splashback radius from cluster gas and observable profiles in the FLAMINGO simulations

The splashback radius, coinciding with the minimum in the dark matter radial density gradient, is thought to be a universal definition of the edge of a dark matter halo. Observational methods to detect it have traced the dark matter using weak gravitational lensing or galaxy number counts. Recent attempts have also claimed the detection of a similar feature in Sunyaev–Zel’dovich (SZ) observations of the hot intracluster gas. Here, we use the FLAMINGO simulations to investigate whether an extremum gradient in a similar position to the splashback radius is predicted to occur in the cluster gas profiles. We find that the minimum in the gradient of the stacked 3D gas density and pressure profiles, and the maximum in the gradient of the entropy profile, broadly align with the splashback feature though there are significant differences. While the dark matter splashback radius varies with specific mass accretion rate, in agreement with previous work, the radial position of the deepest minimum in the log-slope of the gas density is more sensitive to halo mass. In addition, we show that a similar minimum is also present in projected 2D pseudo-observable profiles: emission measure (X-ray), Compton-y (SZ), and surface mass density (weak lensing). We find that the latter traces the dark matter results reasonably well albeit the minimum occurs at a slightly smaller radius. While results for the gas profiles are largely insensitive to accretion rate and various observable proxies for dynamical state, they do depend on the strength of the feedback processes

Inferring the dark matter splashback radius from cluster gas and observable profiles in the FLAMINGO simulations.

The splashback radius, coinciding with the minimum in the dark matter radial density gradient, is thought to be a universal definition of the edge of a dark matter halo. Observational methods to detect it have traced the dark matter using weak gravitational lensing or galaxy number counts. Recent attempts have also claimed the detection of a similar feature in Sunyaev-Zel'dovich (SZ) observations of the hot intracluster gas. Here, we use the FLAMINGO simulations to investigate whether an extremum gradient in a similar position to the splashback radius is predicted to occur in the cluster gas profiles. We find that the minimum in the gradient of the stacked 3D gas density and pressure profiles, and the maximum in the gradient of the entropy profile, broadly align with the splashback feature though there are significant differences. While the dark matter splashback radius varies with specific mass accretion rate, in agreement with previous work, the radial position of the deepest minimum in the log-slope of the gas density is more sensitive to halo mass. In addition, we show that a similar minimum is also present in projected 2D pseudo-observable profiles: emission measure (X-ray); Compton-$y$ (SZ) and surface mass density (weak lensing). We find that the latter traces the dark matter results reasonably well albeit the minimum occurs at a slightly smaller radius. While results for the gas profiles are largely insensitive to accretion rate and various observable proxies for dynamical state, they do depend on the strength of the feedback processes

Impact of baryons on the cluster mass function and cosmological parameter determination

Recent results by the Planck collaboration have shown that cosmological parameters derived from the cosmic microwave background anisotropies and cluster number counts are in tension, with the latter preferring lower values of the matter density parameter, $\Omega_\mathrm{m}$, and power spectrum amplitude, $\sigma_8$. Motivated by this, we investigate the extent to which the tension may be ameliorated once the effect of baryonic depletion on the cluster mass function is taken into account. We use the large-volume Millennium Gas simulations in our study, including one where the gas is pre-heated at high redshift and one where the gas is heated by stars and active galactic nuclei (in the latter, the self-gravity of the baryons and radiative cooling are omitted). In both cases, the cluster baryon fractions are in reasonably good agreement with the data at low redshift, showing significant depletion of baryons with respect to the cosmic mean. As a result, it is found that the cluster abundance in these simulations is around 15 per cent lower than the commonly-adopted fit to dark matter simulations by Tinker et al (2008) for the mass range $10^{14}-10^{14.5}h^{-1} \mathrm{M}_\odot$. Ignoring this effect produces a significant artificial shift in cosmological parameters which can be expressed as $\Delta[\sigma_8(\Omega_\mathrm{m}/0.27)^{0.38}]\simeq -0.03$ at $z=0.17$ (the median redshift of the $\mathit{Planck}$ cluster sample) for the feedback model. While this shift is not sufficient to fully explain the $\mathit{Planck}$ discrepancy, it is clear that such an effect cannot be ignored in future precision measurements of cosmological parameters with clusters. Finally, we outline a simple, model-independent procedure that attempts to correct for the effect of baryonic depletion and show that it works if the baryon-dark matter back-reaction is negligible.Comment: 10 pages, 5 figures, Accepted by MNRA

The FLAMINGO project: revisiting the S8S_8 tension and the role of baryonic physics

A number of recent studies have found evidence for a tension between observations of large-scale structure (LSS) and the predictions of the standard model of cosmology with the cosmological parameters fit to the cosmic microwave background (CMB). The origin of this '$S_8$ tension' remains unclear, but possibilities include new physics beyond the standard model, unaccounted for systematic errors in the observational measurements and/or uncertainties in the role that baryons play. Here we carefully examine the latter possibility using the new FLAMINGO suite of large-volume cosmological hydrodynamical simulations. We project the simulations onto observable harmonic space and compare with observational measurements of the power and cross-power spectra of cosmic shear, CMB lensing, and the thermal Sunyaev-Zel'dovich (tSZ) effect. We explore the dependence of the predictions on box size and resolution, cosmological parameters including the neutrino mass, and the efficiency and nature of baryonic 'feedback'. Despite the wide range of astrophysical behaviours simulated, we find that baryonic effects are not sufficiently large to remove the $S_8$ tension. Consistent with recent studies, we find the CMB lensing power spectrum is in excellent agreement with the standard model, whilst the cosmic shear power spectrum, tSZ effect power spectrum, and the cross-spectra between shear, CMB lensing, and the tSZ effect are all in varying degrees of tension with the CMB-specified standard model. These results suggest that some mechanism is required to slow the growth of fluctuations at late times and/or on non-linear scales, but that it is unlikely that baryon physics is driving this modification.Comment: 26 pages, 12 figures, MNRAS, accepted with minor revision

Gene-Network Analysis Identifies Susceptibility Genes Related to Glycobiology in Autism

The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD), and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD

Digital Health Solutions to Reduce the Burden of Atherosclerotic Cardiovascular Disease Proposed by the CARRIER Consortium

Digital health is a promising tool to support people with an elevated risk for atherosclerotic cardiovascular disease (ASCVD) and patients with an established disease to improve cardiovascular outcomes. Many digital health initiatives have been developed and employed. However, barriers to their large-scale implementation have remained. This paper focuses on these barriers and presents solutions as proposed by the Dutch CARRIER (ie, Coronary ARtery disease: Risk estimations and Interventions for prevention and EaRly detection) consortium. We will focus in 4 sections on the following: (1) the development process of an eHealth solution that will include design thinking and cocreation with relevant stakeholders; (2) the modeling approach for two clinical prediction models (CPMs) to identify people at risk of developing ASCVD and to guide interventions; (3) description of a federated data infrastructure to train the CPMs and to provide the eHealth solution with relevant data; and (4) discussion of an ethical and legal framework for responsible data handling in health care. The Dutch CARRIER consortium consists of a collaboration between experts in the fields of eHealth development, ASCVD, public health, big data, as well as ethics and law. The consortium focuses on reducing the burden of ASCVD. We believe the future of health care is data driven and supported by digital health. Therefore, we hope that our research will not only facilitate CARRIER consortium but may also facilitate other future health care initiatives