Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis

The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. However, the molecular and cellular mechanisms that regulate mucin production and movement are unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), which is generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. Using genetic mouse models, we found that loss of epithelial TNF promoted differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, co-treatment of intestinal organoids with recombinant TNF and a CFTR inhibitor demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF-CFTR signaling axis in the adult intestine and identify epithelial-derived TNF as an upstream regulator of mucin homeostasis

Stress relaxation in the nonequilibrium state of a polymer melt

The influence of entanglement density on the constraint renewal time is studied experimentally in transitory nonequilibrium polymer melts. The entanglement density, as quantified by the rubber elasticity, increases as the linear polymer melt transforms into the equilibrium state. The relaxation modulus obtained from linear step-strain deformations, performed at different points during the equilibration, shows an increase in constraint renewal time as the entanglement density increases. The normalized relaxation modulus curves collapse onto a single curve by rescaling the time axis with a factor (G') over bar (t)(0.9) (where (G') over bar (t) is the normalized instantaneous modulus). These findings suggest that, though the relaxation time increases with the increasing number of entanglements, the mechanism responsible for stress relaxation, after application of step-strain, is similar to that in a fully entangled melt. (C) 2014 The Society of Rheology

A DLG1-ARHGAP31-CDC42 axis is essential for the intestinal stem cell response to fluctuating niche Wnt signaling

A central factor in the maintenance of tissue integrity is the response of stem cells to variations in the levels of niche signals. In the gut, intestinal stem cells (ISCs) depend on Wnt ligands for self-renewal and proliferation. Transient increases in Wnt signaling promote regeneration after injury or in inflammatory bowel diseases, whereas constitutive activation of this pathway leads to colorectal cancer. Here, we report that Discs large 1 (Dlg1), although dispensable for polarity and cellular turnover during intestinal homeostasis, is required for ISC survival in the context of increased Wnt signaling. RNA sequencing (RNA-seq) and genetic mouse models demonstrated that DLG1 regulates the cellular response to increased canonical Wnt ligands. This occurs via the transcriptional regulation of Arhgap31, a GTPase-activating protein that deactivates CDC42, an effector of the non-canonical Wnt pathway. These findings reveal a DLG1-ARHGAP31-CDC42 axis that is essential for the ISC response to increased niche Wnt signaling

Epithelial TNF controls cell differentiation and CFTR activity to maintain intestinal mucin homeostasis

The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and noninflamed samples from patients with inflammatory bowel disease (IBD) undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF/CFTR signaling axis in the adult intestine and identify epithelial cell-derived TNF as an upstream regulator of mucin homeostasis

Unique Rheological Response of Ultrahigh Molecular Weight Polyethylenes in the Presence of Reduced Graphene Oxide

The paper addresses the difference in electrical conductivities and rheological properties between two nanocomposites of reduced graphene oxide nanosheets (rGON) with commercial ultrahigh molecular weight polyethylene (C_PE) and a low-entanglement-density UHMWPE synthesized under controlled conditions (Dis_PE). It has been found that composites made with Dis_PE can reach conductivities at least 100 times higher than those made with C_PE on doing thermal treatment at lower temperatures. However, the difference in the electrical conductivity diminishes when both sets of samples are given a high temperature treatment. This phenomenon is attributed to the difference in morphology of the polymer matrices, for example, grain boundaries between the nascent particles. Furthermore, rheological analyses of the two sets of UHMWPE/rGON nanocomposites conclusively demonstrate differences in the interaction between polyethylene chain segments of the disentangled UHMWPE and rGON, compared to the entangled commercial UHMWPE. Both composites show minima in the storage modulus at a specific graphene composition. The strong interaction of polyethylene chains with the filler inhibits disentangled UHMWPE to achieve the thermodynamic equilibrium melt state, whereas in the commercial sample, having a broader molar mass distribution, the higher adhesion probability of the long chains to the graphene surface lowers the elastic modulus of the polymer melt. Correlation between the percolation threshold for electrical conductivity and rheological response of the composites has also been discussed