Signal transduction pathways involved in proteolysis-inducing factor induced proteasome expression in murine myotubes

The proteolysis-inducing factor (PIF) is produced by cachexia-inducing tumours and initiates protein catabolism in skeletal muscle. The potential signalling pathways linking the release of arachidonic acid (AA) from membrane phospholipids with increased expression of the ubiquitin-proteasome proteolytic pathway by PIF has been studied using C2C12 murine myotubes as a surrogate model of skeletal muscle. The induction of proteasome activity and protein degradation by PIF was blocked by quinacrine, a nonspecific phospholipase A2 (PLA2) inhibitor and trifluroacetyl AA, an inhibitor of cytosolic PLA2. PIF was shown to increase the expression of calcium-independent cytosolic PLA2, determined by Western blotting, at the same concentrations as those inducing maximal expression of 20S proteasome α-subunits and protein degradation. In addition, both U-73122, which inhibits agonist-induced phospholipase C (PLC) activation and D609, a specific inhibitor of phosphatidylcholine-specific PLC also inhibited PIF-induced proteasome activity. This suggests that both PLA 2 and PLC are involved in the release of AA in response to PIF, and that this is important in the induction of proteasome expression. The two tyrosine kinase inhibitors genistein and tryphostin A23 also attenuated PIF-induced proteasome expression, implicating tyrosine kinase in this process. PIF induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) at the same concentrations as that inducing proteasome expression, and the effect was blocked by PD98059, an inhibitor of MAPK kinase, as was also the induction of proteasome expression, suggesting a role for MAPK activation in PIF-induced proteasome expression. © 2003 Cancer Research UK

Bone Mass and Strength in Older Men With Type 2 Diabetes: The Osteoporotic Fractures in Men Study

The effects of type 2 diabetes mellitus (T2DM) on bone volumetric density, bone geometry, and estimates of bone strength are not well established. We used peripheral quantitative computed tomography (pQCT) to compare tibial and radial bone volumetric density (vBMD, mg/cm3), total (ToA, mm2) and cortical (CoA, mm2) bone area and estimates of bone compressive and bending strength in a subset (n = 1171) of men (≥65 years of age) who participated in the multisite Osteoporotic Fractures in Men (MrOS) study. Analysis of covariance–adjusted bone data for clinic site, age, and limb length (model 1) and further adjusted for body weight (model 2) were used to compare data between participants with (n = 190) and without (n = 981) T2DM. At both the distal tibia and radius, patients with T2DM had greater bone vBMD (+2% to +4%, model 1, p < .05) and a smaller bone area (ToA −1% to −4%, model 2, p < .05). The higher vBMD compensated for lower bone area, resulting in no differences in estimated compressive bone strength at the distal trabecular bone regions. At the mostly cortical bone midshaft sites of the radius and tibia, men with T2DM had lower ToA (−1% to −3%, p < .05), resulting in lower bone bending strength at both sites after adjusting for body weight (−2% to −5%, p < .05) despite the lack of difference in cortical vBMD at these sites. These data demonstrate that older men with T2DM have bone strength that is low relative to body weight at the cortical-rich midshaft of the radius despite no difference in cortical vBMD. © 2010 American Society for Bone and Mineral Researc

Cosmoglobe DR1 results. II. Constraints on isotropic cosmic birefringence from reprocessed WMAP and Planck LFI data

Cosmic birefringence is a parity-violating effect that might have rotated the plane of linearly polarized light of the cosmic microwave background (CMB) by an angle $\beta$ since its emission. This has recently been measured to be non-zero at a statistical significance of $3.6\sigma$ in the official Planck PR4 and 9-year WMAP data. In this work, we constrain $\beta$ using the reprocessed BeyondPlanck LFI and Cosmoglobe DR1 WMAP polarization maps. These novel maps have both lower systematic residuals and a more complete error description than the corresponding official products. Foreground $EB$ correlations could bias measurements of $\beta$, and while thermal dust $EB$ emission has been argued to be statistically non-zero, no evidence for synchrotron $EB$ power has been reported. Unlike the dust-dominated Planck HFI maps, the majority of the LFI and WMAP polarization maps are instead dominated by synchrotron emission. Simultaneously constraining $\beta$ and the polarization miscalibration angle, $\alpha$, of each channel, we find a best-fit value of $\beta=0.35^{\circ}\pm0.70^{\circ}$ with LFI and WMAP data only. When including the Planck HFI PR4 maps, but fitting $\beta$ separately for dust-dominated, $\beta_{>70\,\mathrm{GHz}}$, and synchrotron-dominated channels, $\beta_{\leq 70\,\mathrm{GHz}}$, we find $\beta_{\leq 70\,\mathrm{GHz}}=0.53^{\circ}\pm0.28^\circ$. This differs from zero with a statistical significance of $1.9\sigma$, and the main contribution to this value comes from the LFI 70 GHz channel. While the statistical significances of these results are low on their own, the measurement derived from the LFI and WMAP synchrotron-dominated maps agrees with the previously reported HFI-dominated constraints, despite the very different astrophysical and instrumental systematics involved in all these experiments.Comment: 10 pages, 7 figures, 2 tables. Submitted to A&

Cosmoglobe DR1 results. I. Improved Wilkinson Microwave Anisotropy Probe maps through Bayesian end-to-end analysis

We present Cosmoglobe Data Release 1, which implements the first joint analysis of WMAP and Planck LFI time-ordered data, processed within a single Bayesian end-to-end framework. This framework builds directly on a similar analysis of the LFI measurements by the BeyondPlanck collaboration, and approaches the CMB analysis challenge through Gibbs sampling of a global posterior distribution, simultaneously accounting for calibration, mapmaking, and component separation. The computational cost of producing one complete WMAP+LFI Gibbs sample is 812 CPU-hr, of which 603 CPU-hrs are spent on WMAP low-level processing; this demonstrates that end-to-end Bayesian analysis of the WMAP data is computationally feasible. We find that our WMAP posterior mean temperature sky maps and CMB temperature power spectrum are largely consistent with the official WMAP9 results. Perhaps the most notable difference is that our CMB dipole amplitude is $3366.2 \pm 1.4\ \mathrm{\mu K}$, which is $11\ \mathrm{\mu K}$higher than the WMAP9 estimate and$2.5\ {\sigma}$ higher than BeyondPlanck; however, it is in perfect agreement with the HFI-dominated Planck PR4 result. In contrast, our WMAP polarization maps differ more notably from the WMAP9 results, and in general exhibit significantly lower large-scale residuals. We attribute this to a better constrained gain and transmission imbalance model. It is particularly noteworthy that the W-band polarization sky map, which was excluded from the official WMAP cosmological analysis, for the first time appears visually consistent with the V-band sky map. Similarly, the long standing discrepancy between the WMAP K-band and LFI 30 GHz maps is finally resolved, and the difference between the two maps appears consistent with instrumental noise at high Galactic latitudes. All maps and the associated code are made publicly available through the Cosmoglobe web page.Comment: 65 pages, 61 figures. Data available at cosmoglobe.uio.no. Submitted to A&

BeyondPlanck II. CMB map-making through Gibbs sampling

We present a Gibbs sampling solution to the map-making problem for CMB measurements, building on existing destriping methodology. Gibbs sampling breaks the computationally heavy destriping problem into two separate steps; noise filtering and map binning. Considered as two separate steps, both are computationally much cheaper than solving the combined problem. This provides a huge performance benefit as compared to traditional methods, and allows us for the first time to bring the destriping baseline length to a single sample. We apply the Gibbs procedure to simulated Planck 30 GHz data. We find that gaps in the time-ordered data are handled efficiently by filling them with simulated noise as part of the Gibbs process. The Gibbs procedure yields a chain of map samples, from which we may compute the posterior mean as a best-estimate map. The variation in the chain provides information on the correlated residual noise, without need to construct a full noise covariance matrix. However, if only a single maximum-likelihood frequency map estimate is required, we find that traditional conjugate gradient solvers converge much faster than a Gibbs sampler in terms of total number of iterations. The conceptual advantages of the Gibbs sampling approach lies in statistically well-defined error propagation and systematic error correction, and this methodology forms the conceptual basis for the map-making algorithm employed in the BeyondPlanck framework, which implements the first end-to-end Bayesian analysis pipeline for CMB observations.Comment: 11 pages, 10 figures. All BeyondPlanck products and software will be released publicly at http://beyondplanck.science during the online release conference (November 18-20, 2020). Connection details will be made available at the same website. Registration is mandatory for the online tutorial, but optional for the conferenc

BeyondPlanck VII. Bayesian estimation of gain and absolute calibration for CMB experiments

We present a Bayesian calibration algorithm for CMB observations as implemented within the global end-to-end BeyondPlanck (BP) framework, and apply this to the Planck Low Frequency Instrument (LFI) data. Following the most recent Planck analysis, we decompose the full time-dependent gain into a sum of three orthogonal components: One absolute calibration term, common to all detectors; one time-independent term that can vary between detectors; and one time-dependent component that is allowed to vary between one-hour pointing periods. Each term is then sampled conditionally on all other parameters in the global signal model through Gibbs sampling. The absolute calibration is sampled using only the orbital dipole as a reference source, while the two relative gain components are sampled using the full sky signal, including the orbital and Solar CMB dipoles, CMB fluctuations, and foreground contributions. We discuss various aspects of the data that influence gain estimation, including the dipole/polarization quadrupole degeneracy and anomalous jumps in the instrumental gain. Comparing our solution to previous pipelines, we find good agreement in general, with relative deviations of -0.84% (-0.67%) for 30 GHz, -0.14% (0.02%) for 44 GHz and -0.69% (-0.08%) for 70 GHz, compared to Planck 2018 (NPIPE). The deviations we find are within expected error bounds, and we attribute them to differences in data usage and general approach between the pipelines. In particular, the BP calibration is performed globally, resulting in better inter-frequency consistency. Additionally, WMAP observations are used actively in the BP analysis, which breaks degeneracies in the Planck data set and results in better agreement with WMAP. Although our presentation and algorithm are currently oriented toward LFI processing, the procedure is fully generalizable to other experiments.Comment: 18 pages, 15 figures. All BeyondPlanck products and software will be released publicly at http://beyondplanck.science during the online release conference (November 18-20, 2020). Connection details will be made available at the same website. Registration is mandatory for the online tutorial, but optional for the conferenc

BeyondPlanck XII. Cosmological parameter constraints with end-to-end error propagation

We present cosmological parameter constraints as estimated using the Bayesian BeyondPlanck (BP) analysis framework. This method supports seamless end-to-end error propagation from raw time-ordered data to final cosmological parameters. As a first demonstration of the method, we analyze time-ordered Planck LFI observations, combined with selected external data (WMAP 33-61GHz, Planck HFI DR4 353 and 857GHz, and Haslam 408MHz) in the form of pixelized maps which are used to break critical astrophysical degeneracies. Overall, all results are generally in good agreement with previously reported values from Planck 2018 and WMAP, with the largest relative difference for any parameter of about 1 sigma when considering only temperature multipoles between 29<l<601. In cases where there are differences, we note that the BP results are generally slightly closer to the high-l HFI-dominated Planck 2018 results than previous analyses, suggesting slightly less tension between low and high multipoles. Using low-l polarization information from LFI and WMAP, we find a best-fit value of tau=0.066 +/- 0.013, which is higher than the low value of tau=0.051 +/- 0.006 derived from Planck 2018 and slightly lower than the value of 0.069 +/- 0.011 derived from joint analysis of official LFI and WMAP products. Most importantly, however, we find that the uncertainty derived in the BP processing is about 30% larger than when analyzing the official products, after taking into account the different sky coverage. We argue that this is due to marginalizing over a more complete model of instrumental and astrophysical parameters, and this results in both more reliable and more rigorously defined uncertainties. We find that about 2000 Monte Carlo samples are required to achieve robust convergence for low-resolution CMB covariance matrix with 225 independent modes.Comment: 13 pages, 10 figure

BeyondPlanck XIV. Polarized foreground emission between 30 and 70GHz

We constrain polarized foreground emission between 30 and 70GHz with the Planck Low Frequency Instrument (LFI) and WMAP data within the framework of BeyondPlanck global Bayesian analysis. We combine for the first time full-resolution Planck LFI time-ordered data with low-resolution WMAP sky maps at 33, 40 and 61GHz. Spectral parameters are fit with a likelihood defined at the native resolution of each frequency channel. This analysis represents the first implementation of true multi-resolution component separation applied to CMB observations for both amplitude and spectral energy distribution (SED) parameters. For synchrotron emission, we approximate the SED as a power-law in frequency and find that the low signal-to-noise ratio of the data set strongly limits the number of free parameters that may be robustly constrained. We partition the sky into four large disjoint regions (High Latitude; Galactic Spur; Galactic Plane; and Galactic Center), each associated with its own power-law index. We find that the High Latitude region is prior-dominated, while the Galactic Center region is contaminated by residual instrumental systematics. The two remaining regions appear to be both signal-dominated and clean of systematics, and for these we derive spectral indices of $\beta_{\mathrm s}^{\mathrm{Spur}}=-3.15\pm0.07$ and $\beta_{\mathrm s}^{\mathrm{Plane}}=-3.12\pm0.06$. This agrees qualitatively with the WMAP-only polarization constraints presented by Dunkley et al. (2009), but contrasts with several temperature-based analyses. For thermal dust emission we assume a modified blackbody model and we fit the power-law index across the full sky. We find $\beta_{\mathrm{d}}=1.62\pm0.04$, which is slightly steeper than that previously reported from Planck HFI data, but still statistically consistent at a 2$\sigma$ confidence level.Comment: 17 pages, 14 figures. All BeyondPlanck products and software will be released publicly at http://beyondplanck.science during the online release conference (November 18-20, 2020). Connection details will be made available at the same website. Registration is mandatory for the online tutorial, but optional for the conferenc

BeyondPlanck X. Planck LFI frequency maps with sample-based error propagation

We present Planck LFI frequency sky maps derived within the BeyondPlanck framework. This framework draws samples from a global posterior distribution that includes instrumental, astrophysical and cosmological parameters, and the main product is an entire ensemble of frequency sky map samples. This ensemble allows for computationally convenient end-to-end propagation of low-level instrumental uncertainties into higher-level science products. We show that the two dominant sources of LFI instrumental systematic uncertainties are correlated noise and gain fluctuations, and the products presented here support - for the first time - full Bayesian error propagation for these effects at full angular resolution. We compare our posterior mean maps with traditional frequency maps delivered by the Planck collaboration, and find generally good agreement. The most important quality improvement is due to significantly lower calibration uncertainties in the new processing, as we find a fractional absolute calibration uncertainty at 70 GHz of $\delta g_{0}/g_{0} =5 \cdot 10^{-5}$, which is nominally 40 times smaller than that reported by Planck 2018. However, the original Planck 2018 estimate has a non-trivial statistical interpretation, and this further illustrates the advantage of the new framework in terms of producing self-consistent and well-defined error estimates of all involved quantities without the need of ad hoc uncertainty contributions. We describe how low-resolution data products, including dense pixel-pixel covariance matrices, may be produced directly from the posterior samples without the need for computationally expensive analytic calculations or simulations. We conclude that posterior-based frequency map sampling provides unique capabilities in terms of low-level systematics modelling and error propagation, and may play an important role for future CMB B-mode experiments. (Abridged.)Comment: 32 pages, 23 figures, data available from https://www.cosmoglobe.uio.no