SWI/SNF regulates a transcriptional programme that induces senescence to prevent liver cancer

Oncogene-induced senescence (OIS) is a potent tumour suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumours. ARID1B controls p16INK4a and p21CIP1a transcription but also regulates DNA damage, oxidative stress and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that pro-senescence therapies could be employed against SWI/SNF-mutated cancers

Molecular dynamics for linear polymer melts in bulk and confined systems under shear flow

In this work, we analyzed the individual chain dynamics for linear polymer melts under shear flow for bulk and confined systems using atomistic nonequilibrium molecular dynamics simulations of unentangled (C50H102) and slightly entangled (C178H358) polyethylene melts. While a certain similarity appears for the bulk and confined systems for the dynamic mechanisms of polymer chains in response to the imposed flow field, the interfacial chain dynamics near the boundary solid walls in the confined system are significantly different from the corresponding bulk chain dynamics. Detailed molecular-level analysis of the individual chain motions in a wide range of flow strengths are carried out to characterize the intrinsic molecular mechanisms of the bulk and interfacial chains in three flow regimes (weak, intermediate, and strong). These mechanisms essentially underlie various macroscopic structural and rheological properties of polymer systems, such as the mean-square chain end-to-end distance, probability distribution of the chain end-to-end distance, viscosity, and the first normal stress coefficient. Further analysis based on the mesoscopic Brightness method provides additional structural information about the polymer chains in association with their molecular mechanisms

The effect of temperature gradients on the sharkskin surface instability in polymer extrusion through a slit die

The sharkskin surface instability is commonly observed in the extrusion of polymer melts. We present a series of experiments in which a specifically designed rectangular slit die with insulated and independently heated sides and is used to induce precise temperature gradients across a flowing polyethylene melt. Our previous experiments demonstrated that the character of the surface distortions produced by the sharkskin instability was a function of the die wall temperature and therefore the extrudate had viscoelastic properties at the surface. In this paper, we explore the role of temperature and viscoelastic property gradients near the capillary wall. The amplitude of the sharkskin instability is quantified and plotted against apparent shear and extension rates. Analysis of the data demonstrates that the amplitude and frequency of the instability is independent of bulk temperature and temperature gradient and is dependent only on wall temperature. The data are normalized using a dimensionless Weissenberg number based on the extension rate to collapse the data collected over all temperatures and gradients onto a single master curve. We conclude with an example of a rectangular extrudate exhibiting varying surface roughness due to differential die heating and discuss the implications of our observations on the sharkskin surface instability mechanism and on commercial application