Dystropathology increases energy expenditure and protein turnover in the mdx mouse model of Duchenne muscular dystrophy

The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old) and adult (12- to 14-wk-old) male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing) adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles

p21WAF1/CIP1 Upregulation through the Stress Granule-Associated Protein CUGBP1 Confers Resistance to Bortezomib-Mediated Apoptosis

p21(WAF1/CIP1) is a well known cyclin-dependent kinase inhibitor induced by various stress stimuli. Depending on the stress applied, p21 upregulation can either promote apoptosis or prevent against apoptotic injury. The stress-mediated induction of p21 involves not only its transcriptional activation but also its posttranscriptional regulation, mainly through stabilization of p21 mRNA levels. We have previously reported that the proteasome inhibitor MG132 induces the stabilization of p21 mRNA, which correlates with the formation of cytoplasmic RNA stress granules. The mechanism underlying p21 mRNA stabilization, however, remains unknown.We identified the stress granules component CUGBP1 as a factor required for p21 mRNA stabilization following treatment with bortezomib ( =  PS-341/Velcade). This peptide boronate inhibitor of the 26S proteasome is very efficient for the treatment of myelomas and other hematological tumors. However, solid tumors are sometimes refractory to bortezomib treatment. We found that depleting CUGBP1 in cancer cells prevents bortezomib-mediated p21 upregulation. FISH experiments combined to mRNA stability assays show that this effect is largely due to a mistargeting of p21 mRNA in stress granules leading to its degradation. Altering the expression of p21 itself, either by depleting CUGBP1 or p21, promotes bortezomib-mediated apoptosis.We propose that one key mechanism by which apoptosis is inhibited upon treatment with chemotherapeutic drugs might involve upregulation of the p21 protein through CUGBP1

The IceCube Neutrino Observatory - Contributions to ICRC 2017 Part VI: IceCube-Gen2, the Next Generation Neutrino Observatory

Papers on research & development towards IceCube-Gen2, the next generation neutrino observatory at South Pole, submitted to the 35th International Cosmic Ray Conference (ICRC 2017, Busan, South Korea) by the IceCube-Gen2 Collaboration

RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation

International audienceAdipose tissue structure is altered during obesity, leading to deregulation of whole-body metabolism. Its function depends on its structure, in particular adipocytes number and differentiation stage. To better understand the mechanisms regulating adipogenesis, we have investigated the role of an endoribonuclease, endoribonuclease L (RNase L), using wild-type and RNase L-knockout mouse embryonic fibroblasts (RNase L À/À-MEFs). Here, we identify C/EBP homologous protein 10 (CHOP10), a dominant negative member of the CCAAT/enhancer-binding protein family, as a specific RNase L target. We show that RNase L is associated with CHOP10 mRNA and regulates its stability. CHOP10 expression is conserved in RNase L À/À-MEFs, maintaining preadipocyte state while impairing their terminal differentiation. RNase L À/À-MEFs have decreased lipids storage capacity, insulin sensitivity and glucose uptake. Expression of ectopic RNase L in RNase L À/À-MEFs triggers CHOP10 mRNA instability, allowing increased lipids storage, insulin response and glucose uptake. Similarly, downregulation of CHOP10 mRNA with CHOP10 siRNA in RNase L À/À-MEFs improves their differentiation in adipocyte. In vivo, aged RNase L À / À mice present an expanded adipose tissue, which, however, is unable to correctly store lipids, illustrated by ectopic lipids storage in the liver and in the kidney. These findings highlight RNase L as an essential regulator of adipogenesis via the regulation of CHOP10 mRNA

Measurements of the time-dependent cosmic-ray Sun shadow with seven years of IceCube data: Comparison with the Solar cycle and magnetic field models

© 2021 American Physical Society. Observations of the time-dependent cosmic-ray Sun shadow have been proven as a valuable diagnostic for the assessment of solar magnetic field models. In this paper, seven years of IceCube data are compared to solar activity and solar magnetic field models. A quantitative comparison of solar magnetic field models with IceCube data on the event rate level is performed for the first time. Additionally, a first energy-dependent analysis is presented and compared to recent predictions. We use seven years of IceCube data for the moon and the Sun and compare them to simulations on data rate level. The simulations are performed for the geometrical shadow hypothesis for the moon and the Sun and for a cosmic-ray propagation model governed by the solar magnetic field for the case of the Sun. We find that a linearly decreasing relationship between Sun shadow strength and solar activity is preferred over a constant relationship at the 6.4σ level. We test two commonly used models of the coronal magnetic field, both combined with a Parker spiral, by modeling cosmic-ray propagation in the solar magnetic field. Both models predict a weakening of the shadow in times of high solar activity as it is also visible in the data. We find tensions with the data on the order of 3σ for both models, assuming only statistical uncertainties. The magnetic field model CSSS fits the data slightly better than the PFSS model. This is generally consistent with what is found previously by the Tibet AS-γ Experiment; a deviation of the data from the two models is, however, not significant at this point. Regarding the energy dependence of the Sun shadow, we find indications that the shadowing effect increases with energy during times of high solar activity, in agreement with theoretical predictions

Search for high-energy neutrinos from ultraluminous infrared galaxies with icecube

Ultraluminous infrared galaxies (ULIRGs) have infrared luminosities LIR ≥ 1012L⊙, making them the most luminous objects in the infrared sky. These dusty objects are generally powered by starbursts with star formation rates that exceed 100 M⊙ yr−1, possibly combined with a contribution from an active galactic nucleus. Such environments make ULIRGs plausible sources of astrophysical high-energy neutrinos, which can be observed by the IceCube Neutrino Observatory at the South Pole. We present a stacking search for high-energy neutrinos from a representative sample of 75 ULIRGs with redshift z ≤ 0.13 using 7.5 yr of IceCube data. The results are consistent with a background-only observation, yielding upper limits on the neutrino flux from these 75 ULIRGs. For an unbroken E−2.5 power-law spectrum, we report an upper limit on the stacked flux ${{\rm{\Phi }}}_{{\nu }_{\mu }+{\bar{\nu }}_{\mu }}^{90 \% }=3.24\times {10}^{-14}\,{\mathrm{TeV}}^{-1}\,{\mathrm{cm}}^{-2}\,{{\rm{s}}}^{-1}\,{(E/10\,\mathrm{TeV})}^{-2.5}$ at 90% confidence level. In addition, we constrain the contribution of the ULIRG source population to the observed diffuse astrophysical neutrino flux as well as model predictions

Measurements of the time-dependent cosmic-ray Sun shadow with seven years of IceCube data: Comparison with the Solar cycle and magnetic field models

Observations of the time-dependent cosmic-ray Sun shadow have been proven as a valuable diagnostic for the assessment of solar magnetic field models. In this paper, seven years of IceCube data are compared to solar activity and solar magnetic field models. A quantitative comparison of solar magnetic field models with IceCube data on the event rate level is performed for the first time. Additionally, a first energy-dependent analysis is presented and compared to recent predictions. We use seven years of IceCube data for the moon and the Sun and compare them to simulations on data rate level. The simulations are performed for the geometrical shadow hypothesis for the moon and the Sun and for a cosmic-ray propagation model governed by the solar magnetic field for the case of the Sun. We find that a linearly decreasing relationship between Sun shadow strength and solar activity is preferred over a constant relationship at the 6.4σ level. We test two commonly used models of the coronal magnetic field, both combined with a Parker spiral, by modeling cosmic-ray propagation in the solar magnetic field. Both models predict a weakening of the shadow in times of high solar activity as it is also visible in the data. We find tensions with the data on the order of 3σ for both models, assuming only statistical uncertainties. The magnetic field model CSSS fits the data slightly better than the PFSS model. This is generally consistent with what is found previously by the Tibet AS-γ Experiment; a deviation of the data from the two models is, however, not significant at this point. Regarding the energy dependence of the Sun shadow, we find indications that the shadowing effect increases with energy during times of high solar activity, in agreement with theoretical predictions

Search for PeV Gamma-Ray Emission from the Southern Hemisphere with 5 Yr of Data from the IceCube Observatory

The measurement of diffuse PeV gamma-ray emission from the Galactic plane would provide information about the energy spectrum and propagation of Galactic cosmic rays, and the detection of a pointlike source of PeV gamma-rays would be strong evidence for a Galactic source capable of accelerating cosmic rays up to at least a few PeV. This paper presents several unbinned maximum-likelihood searches for PeV gamma-rays in the Southern Hemisphere using 5 yr of data from the IceTop air shower surface detector and the in-ice array of the IceCube Observatory. The combination of both detectors takes advantage of the low muon content and deep shower maximum of gamma-ray air showers and provides excellent sensitivity to gamma-rays between ∼0.6 and 100 PeV. Our measurements of pointlike and diffuse Galactic emission of PeV gamma-rays are consistent with the background, so we constrain the angle-integrated diffuse gamma-ray flux from the Galactic plane at 2 PeV to 2.61 × 10-19 cm-2 s-1 TeV-1 at 90% confidence, assuming an E -3 spectrum, and we estimate 90% upper limits on pointlike emission at 2 PeV between 10-21 and 10-20 cm-2 s-1 TeV-1 for an E -2 spectrum, depending on decl. Furthermore, we exclude unbroken power-law emission up to 2 PeV for several TeV gamma-ray sources observed by the High Energy Spectroscopic System and calculate upper limits on the energy cutoffs of these sources at 90% confidence. We also find no PeV gamma-rays correlated with neutrinos from IceCube's high-energy starting event sample. These are currently the strongest constraints on PeV gamma-ray emission