Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase: effect on Mdm2 binding

The p53 tumor suppressor protein is stabilized in response to ionizing radiation and accumulates in the nucleus. Stabilization is thought to involve disruption of the interaction between the p53 protein and Mdm2, which targets p53 for degradation. Here we show that the direct association between a p53 N-terminal peptide and Mdm2 is disrupted by phosphorylation of the peptide on Thr18 but not by phosphorylation at other N-terminal sites, including Ser15 and Ser37. Thr18 was phosphorylated in vitro by casein kinase (CK1); this process required the prior phosphorylation of Ser15. Thr18 was phosphorylated in vivo in response to DNA damage, and such phosphorylation required Ser15. Our results suggest that stabilization of p53 after ionizing radiation may result, in part, from an inhibition of Mdm2 binding through a phosphorylation-phosphorylation cascade involving DNA damage-activated phosphorylation of p53 Ser15 followed by phosphorylation of Thr18

New constraints on cosmological modified gravity theories from anisotropic three-point correlation functions of BOSS DR12 galaxies

We report a new test of modified gravity theories using the large-scale structure of the Universe. This paper is the first attempt to (1) apply a joint analysis of the anisotropic components of galaxy two- and three-point correlation functions (2 and 3PCFs) to actual galaxy data and (2) constrain the nonlinear effects of degenerate higher-order scalar-tensor (DHOST) theories on cosmological scales. Applying this analysis to the Baryon Oscillation Spectroscopic Survey (BOSS) data release 12, we obtain the lower bounds of $-1.655 < \xi_{\rm t}$ and $-0.504 < \xi_{\rm s}$ at the $95\%$ confidence level on the parameters characterising the time evolution of the tidal and shift terms of the second-order velocity field. These constraints are consistent with GR predictions of $\xi_{\rm t}=15/1144$ and $\xi_{\rm s}=0$. Moreover, they represent a $35$-fold and $20$-fold improvement, respectively, over the joint analysis with only the isotropic 3PCF. We ensure the validity of our results by investigating various quantities, including theoretical models of the 3PCF, window function corrections, cumulative ${\rm S/N}$, Fisher matrices, and statistical scattering effects of mock simulation data. We also find statistically significant discrepancies between the BOSS data and the Patchy mocks for the 3PCF measurement. Finally, we package all of our 3PCF analysis codes under the name \textsc{HITOMI} and make them publicly available so that readers can reproduce all the results of this paper and easily apply them to ongoing future galaxy surveys.Comment: 60 pages, 21 figures, 22 tables; a set of codes for data analysis is publicly available at https://github.com/naonori/hitomi.gi

First test of the consistency relation for the large-scale structure using the anisotropic three-point correlation function of BOSS DR12 galaxies (An explanatory video is available at https://youtu.be/Zi36ooLPhss.)

We present, for the first time, an observational test of the consistency relation for the large-scale structure (LSS) of the Universe through a joint analysis of the anisotropic two- and three-point correlation functions (2PCF and 3PCF) of galaxies. We parameterise the breakdown of the LSS consistency relation in the squeezed limit by $E_{\rm s}$, which represents the ratio of the coefficients of the shift terms in the second-order density and velocity fluctuations. $E_{\rm s}\neq1$ is a sufficient condition under which the LSS consistency relation is violated. A novel aspect of this work is that we constrain $E_{\rm s}$ by obtaining information about the nonlinear velocity field from the quadrupole component of the 3PCF without taking the squeezed limit. Using the galaxy catalogues in the Baryon Oscillation Spectroscopic Survey (BOSS) Data Release 12, we obtain $E_{\rm s} = -0.92_{-3.26}^{+3.13}$, indicating that there is no violation of the LSS consistency relation in our analysis within the statistical errors. Our parameterisation is general enough that our constraint can be applied to a wide range of theories, such as multicomponent fluids, modified gravity theories, and their associated galaxy bias effects. Our analysis opens a new observational window to test the fundamental physics using the anisotropic higher-order correlation functions of galaxy clustering.Comment: 17 pages, 6 figures. Explanatory videos are available in several languages: https://youtu.be/Zi36ooLPhss (English), https://youtu.be/d2ZamcDt6hs (French), https://youtu.be/iSm5yPWmZ9c (Spanish), https://youtu.be/Go7ox-ciHIc (German), https://youtu.be/6Ith7cE723o (Chinese), and https://youtu.be/rH9-C3eKoYc (English with my voice

Alleviating Surgeons’ Stress through Listening to Natural Sounds in a Half-Encapsulated Rest Space after an Operation: A Pilot, Longitudinal Field Study

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Antisense PMO Found in Dystrophic Dog Model Was Effective in Cells from Exon 7-Deleted DMD Patient

BACKGROUND: Antisense oligonucleotide-induced exon skipping is a promising approach for treatment of Duchenne muscular dystrophy (DMD). We have systemically administered an antisense phosphorodiamidate morpholino oligomer (PMO) targeting dystrophin exons 6 and 8 to a dog with canine X-linked muscular dystrophy in Japan (CXMD(J)) lacking exon 7 and achieved recovery of dystrophin in skeletal muscle. To date, however, antisense chemical compounds used in DMD animal models have not been directly applied to a DMD patient having the same type of exon deletion. We recently identified a DMD patient with an exon 7 deletion and tried direct translation of the antisense PMO used in dog models to the DMD patient's cells. METHODOLOGY/PRINCIPAL FINDINGS: We converted fibroblasts of CXMD(J) and the DMD patient to myotubes by FACS-aided MyoD transduction. Antisense PMOs targeting identical regions of dog and human dystrophin exons 6 and 8 were designed. These antisense PMOs were mixed and administered as a cocktail to either dog or human cells in vitro. In the CXMD(J) and human DMD cells, we observed a similar efficacy of skipping of exons 6 and 8 and a similar extent of dystrophin protein recovery. The accompanying skipping of exon 9, which did not alter the reading frame, was different between cells of these two species. CONCLUSION/SIGNIFICANCE: Antisense PMOs, the effectiveness of which has been demonstrated in a dog model, achieved multi-exon skipping of dystrophin gene on the FACS-aided MyoD-transduced fibroblasts from an exon 7-deleted DMD patient, suggesting the feasibility of systemic multi-exon skipping in humans