Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing

The cyclin-dependent kinase inhibitor p21WAF1/CIP1 (p21) is a cell-cycle checkpoint effector and inducer of senescence, regulated by p53. Yet, evidence suggests that p21 could also be oncogenic, through a mechanism that has so far remained obscure. We report that a subset of atypical cancerous cells strongly expressing p21 showed proliferation features. This occurred predominantly in p53-mutant human cancers, suggesting p53-independent upregulation of p21 selectively in more aggressive tumour cells. Multifaceted phenotypic and genomic analyses of p21-inducible, p53-null, cancerous and near-normal cellular models showed that after an initial senescence-like phase, a subpopulation of p21-expressing proliferating cells emerged, featuring increased genomic instability, aggressiveness and chemoresistance. Mechanistically, sustained p21 accumulation inhibited mainly the CRL4–CDT2 ubiquitin ligase, leading to deregulated origin licensing and replication stress. Collectively, our data reveal the tumour-promoting ability of p21 through deregulation of DNA replication licensing machinery—an unorthodox role to be considered in cancer treatment, since p21 responds to various stimuli including some chemotherapy drugs

On the Stability of Subsonic Impinging Jets

Impinging jets are relevant in many applications, especially those involving heating and cooling processes. In such context, several techniques have been proposed to enhance the heat transfer at the wall: in particular, experimental investigations demonstrated that the use of a pulsating inlet with an appropriate pulsation frequency may result in a 40% enhancement of heat transfer compared to a non-pulsating configuration. Such a result is related to the enlargement of the generated toroidal vortices which cause higher wall shear stresses. The mechanism underlying the generation of these larger vortex rings at a specific frequency is still unclear and the explanation of the effects of pulsation on heat transfer is still an open question. In order to shed light on such process, in this work, we present a modal analysis of a subsonic impinging jet confined between two horizontal walls placed at a distance of 5D, being D the diameter of the orifice in the uppermost wall from which the jet issues. Initially, a direct numerical simulation (DNS) of a round jet with a Mach number of 0.8 and a Reynolds number of 3300 is performed and the main flow characteristics (including dominant frequencies and spatial features) are retrieved through a dynamic mode decomposition (DMD) analysis. Subsequently, a global stability analysis on the same physical configuration is carried out and the spatial structures and frequencies of the resulting leading unstable modes are discussed and compared with the DMD and DNS data