Elevated VMP1 expression in acute myeloid leukemia amplifies autophagy and is protective against venetoclax-induced apoptosis

© 2019, The Author(s). Vacuole membrane protein (VMP1) is a putative autophagy protein, which together with Beclin-1 acts as a molecular switch in activating autophagy. In the present study the role of VMP1 was analysed in CD34+ cells of cord blood (CB) and primary acute myeloid leukemia (AML) cells and cell lines. An increased expression of VMP1 was observed in a subset of AML patients. Functional studies in normal CB CD34+ cells indicated that inhibiting VMP1 expression reduced autophagic-flux, coinciding with reduced expansion of hematopoietic stem and progenitor cells (HSPC), delayed differentiation, increased apoptosis and impaired in vivo engraftment. Comparable results were observed in leukemic cell lines and primary AML CD34+ cells. Ultrastructural analysis indicated that leukemic cells overexpressing VMP1 displayed a reduced number of mitochondrial structures, while the number of lysosomal degradation structures was increased. The overexpression of VMP1 did not affect cell proliferation and differentiation, but increased autophagic-flux and improved mitochondrial quality, which coincided with an increased threshold for venetoclax-induced loss of mitochondrial outer membrane permeabilization (MOMP) and apoptosis. In conclusion, our data indicate that in leukemic cells high VMP1 is involved with mitochondrial quality control

Wide shear zones and the spot model: Implications from the split-bottom geometry

The spot model has been developed by Bazant and co-workers to describe quasistatic granular flows. It assumes that granular flow is caused by the opposing flow of so-called spots of excess free volume, with spots moving along the slip lines of Mohr-Coulomb plasticity. The model is two-dimensional and has been successfully applied to a number of different geometries. In this paper we investigate whether the spot model in its simplest form can describe the wide shear zones observed in experiments and simulations of a Couette cell with split bottom. We give a general argument that is independent of the particular description of the stresses, but which shows that the present formulation of the spot model in which diffusion and drift terms are postulated to balance on length scales of order of the spot diameter, i.e. of order 3-5 grain diameters, is difficult to reconcile with the observed wide shear zones. We also discuss the implications for the spot model of co-axiality of the stress and strain rate tensors found in these wide shear flows, and point to possible extensions of the model that might allow one to account for the existence of wide shear zones.Comment: 6 pages, 6 figures, to be published in EPJ

Correlations of strain and plasticity in a flowing foam

Via simulations of flowing foam, we connect the high- and intermediate-density regimes of complex fluid flows into a consistent microscopic picture of deformation. While at and above the jamming transition, elastic correlations lead to a strong spatial organization of the flow field, below jamming, the slowly diminishing elastic correlation length leads to a slowly ceasing spatial organization, which is nevertheless still present down to densities far below jamming. We show that the long-range–correlated flow field arises from the superposition of quadrupolar strain fields of shear zones with highly correlated positions, strengths and orientation. These interactions are still pertinent below jamming, where they systematically weaken with the slowly diminishing elastic correlation length. These results demonstrate the ubiquity and importance of elastic correlations in the flow of complex fluids even below the jamming transition, and motivate a scale-bridging description of their flow over wide ranges of density from solid to fluid

Fluctuations in flows near jamming

Bubbles, droplets or particles in flowing complex media such as foams, emulsions or suspensions follow highly complex paths, with the relative motion of the constituents setting the energy dissipation rate. What is their dynamics, and how is this connected to the global rheology? To address these questions, we probe the statistics and spatio-temporal organization of the local particle motion and energy dissipation in a model for sheared disordered materials. We find that the fluctuations in the local dissipation vary from nearly Gaussian and homogeneous at low densities and fast flows, to strongly intermittent for large densities and slow flows. The higher order moments of the relative particle velocities reveal strong evidence for a qualitative difference between two distinct regimes which are nevertheless connected by a smooth crossover. In the critical regime, the higher order moments are related by novel multiscaling relations. In the plastic regime the relations between these moments take on a different form, with higher moments diverging rapidly when the flow rate vanishes. As these velocity differences govern the energy dissipation, we can distinguish two qualitatively different types of flow: an intermediate density, critical regime related to jamming, and a large density, plastic regime

Correlations of strain and plasticity in a flowing foam

Via simulations of flowing foam, we connect the high and intermediate density regimes of complex fluid flows into a consistent microscopic picture of deformation. While at and above the jamming transition, elastic correlations lead to strong spatial organization of the flow field, below jamming, the slowly diminishing elastic correlation length leads to slowly ceasing spatial organization, which is nevertheless still present down to densities far below jamming. We show that the long-range correlated flow field arises from the superposition of quadrupolar strain fields of shear zones with highly correlated positions, strengths and orientation. These interactions are still pertinent below jamming, where they systematically weaken with the slowly diminishing elastic correlation length. These results demonstrate the ubiquity and importance of elastic correlations in the flow of complex fluids even below the jamming transition, and motivate a scale-bridging description of their flow over wide ranges of density from solid to fluid.Comment: 5 page