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The Hedgehog (Hh) signaling regulates tissue development, and its aberrant activation is a leading cause of malignancies, including medulloblastoma (Mb). Hh-dependent tumorigenesis often occurs in synergy with other mechanisms, such as loss of p53, the master regulator of the DNA damage response. To date, little is known about mechanisms connecting DNA-damaging events to morphogen-dependent processes. Here, we show that genotoxic stress triggers a cascade of signals, culminating with inhibition of the activity of Gli1, the final transcriptional effector of Hh signaling. This inhibition is dependent on the p53-mediated elevation of the acetyltransferase p300/CBP-associated factor (PCAF). Notably, we identify PCAF as a novel E3 ubiquitin ligase of Gli1. Indeed PCAF, but not a mutant with a deletion of its ubiquitination domain, represses Hh signaling in response to DNA damage by promoting Gli1 ubiquitination and its proteasome-dependent degradation. Restoring Gli1 levels rescues the growth arrest and apoptosis effect triggered by genotoxic drugs. Consistently, DNA-damaging agents fail to inhibit Gli1 activity in the absence of either p53 or PCAF. Finally, Mb samples from p53-null mice display low levels of PCAF and upregulation of Gli1 in vivo, suggesting PCAF as potential therapeutic target in Hh-dependent tumors. Together, our data define a mechanism of inactivation of a morphogenic signaling in response to genotoxic stress and unveil a p53/PCAF/Gli1 circuitry centered on PCAF that limits Gli1-enhanced mitogenic and prosurvival response. [ABSTRACT FROM AUTHOR]

The characterization of a temporal filter based on cross-polarized wave generation working in the few-optical-cycle regime is presented. We show that this device dramatically improves the spectral quality of the ultrashort seed pulses, opening the way to the production of sub-10 fs pulses with high incoherent and coherent contrast. The dispersion compensation conditions for an optimized behavior of the process are experimentally and theoretically discussed. [ABSTRACT FROM AUTHOR]

Cross-polarized wave (XPW) generation is used for the contrast improvement of ultra-intense femtosecond laser pulses in a double CPA configuration. We present theoretical and experimental evidence that the XPW output spectrum depends in a predictable way on the input chirp. Therefore, a chirp controlled pulse can experience a pulse duration shortening up to a factor of $\sqrt{3}$ , and an initial amount of chirp that leads to the exact preservation of the spectral width of a given pulse can be predicted. [ABSTRACT FROM AUTHOR]

Holographic interferometry is examined for its potential as a diagnostic tool of the structural modifications effected in laser-processing applications. The interferometric ‘comparison’ of the holographic images of the sample recorded before and after irradiation enables the full-field spatially resolved detection of the induced structural modifications. The potential of the method is illustrated in the ablation of polymer (polymethylmethacrylate and polystyrene) films with nanosecond pulses at 193 and 248 nm. The detailed characterization and quantitative monitoring of the growth of the induced modifications as a function of laser-material parameters is attained. A most novel result is the observation of delocalised structural modifications at distances relatively far away (d≈2 cm) from the irradiated area. [ABSTRACT FROM AUTHOR]