Ultrafast decay processes detected after absorption of UV radiation in gas-phase pyrimidine nucleobases uracil, thymine, and cytosine are ascribed to the barrierless character of the pathway along the low-lying 1(pipi*) hypersurface connecting the Franck-Condon region with an out-of-plane distorted ethene-like conical intersection with the ground state. Longer lifetime decays and low quantum yield emission are on the other hand related to the presence of a 1(pipi*) state planar minimum on the S1 surface and the barriers to access other conical intersections. A unified model for the three systems is established on the basis of accurate multiconfigurational CASPT2 calculations, whereas the effect of the different levels of theory on the results is carefully analyzed.

NOTCH1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL) and recently have been found in non-small cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated NOTCH1 in the lung by developing a transgenic mouse model in which activated NOTCH1 was overexpressed in the alveolar epithelium. The initial response to activated NOTCH1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas arose in the transgenic mice, but failed to progress to carcinoma. Interestingly, MYC and MYCL1 were expressed in the adenomas, suggesting that selection for enhanced MYC activity may facilitate tumorigenesis. Using mice engineered to co-express activated NOTCH1 and MYC, we found that supplementing MYC expression increased the frequency of N1ICD-induced adenomas and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by MYC and/or activated NOTCH1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated NOTCH1 substitutes for RAS activation in cooperation with MYC in the development of NSCLC. These tumor models should be valuable for exploring the role of activated NOTCH1 in the genesis of NSCLC and for testing therapies targeting either activated NOTCH1 or its downstream effectors.