AKR1C enzymes sustain therapy resistance in paediatric T-ALL

BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy

Light interception principally drives the understory response to boxelder invasion in riparian forests

Since several decades, American boxelder (Acer negundo) is replacing white willow (Salix alba) riparian forests along southern European rivers. This study aims to evaluate the consequences of boxelder invasion on understory community in riparian areas. We determined the understory species richness, composition and biomass in boxelder and white willow stands located in three riparian forests, representative of three rivers with distinct hydrological regimes. We investigated correlation of these variables to soil moisture and particle size, main soil nutrient stocks, potential nitrification and denitrification, tree canopy cover and photosynthetic active radiation (PAR) at the ground level. A greenhouse experiment was then conducted to identify the causal factors responsible for changes in the understory. The effect of soil type, PAR level and water level on the growth and the biomass production of Urtica dioica were examined. A lower plant species richness and biomass, and a modification of community composition were observed for boxelder understory in all sites, regardless of their environmental characteristics. The strongest modification that follows boxelder invasion was the decline in U. dioica, the dominant species of the white willow forest understory. These differences were mainly correlated with a lower incident PAR under boxelder canopy. The greenhouse experiment identified PAR level as the main factor responsible for the changes in U. dioica stem number and biomass. Our results indicate that adult boxelder acts as an ecosystem engineer that decreases light availability. The opportunistic invasion by boxelder leads to important understory changes, which could alter riparian ecosystem functioning

ANK, a Host Cytoplasmic Receptor for the Tobacco mosaic virus Cell-to-Cell Movement Protein, Facilitates Intercellular Transport through Plasmodesmata

Plasmodesma (PD) is a channel structure that spans the cell wall and provides symplastic connection between adjacent cells. Various macromolecules are known to be transported through PD in a highly regulated manner, and plant viruses utilize their movement proteins (MPs) to gate the PD to spread cell-to-cell. The mechanism by which MP modifies PD to enable intercelluar traffic remains obscure, due to the lack of knowledge about the host factors that mediate the process. Here, we describe the functional interaction between Tobacco mosaic virus (TMV) MP and a plant factor, an ankyrin repeat containing protein (ANK), during the viral cell-to-cell movement. We utilized a reverse genetics approach to gain insight into the possible involvement of ANK in viral movement. To this end, ANK overexpressor and suppressor lines were generated, and the movement of MP was tested. MP movement was facilitated in the ANK-overexpressing plants, and reduced in the ANK-suppressing plants, demonstrating that ANK is a host factor that facilitates MP cell-to-cell movement. Also, the TMV local infection was largely delayed in the ANK-suppressing lines, while enhanced in the ANK-overexpressing lines, showing that ANK is crucially involved in the infection process. Importantly, MP interacted with ANK at PD. Finally, simultaneous expression of MP and ANK markedly decreased the PD levels of callose, β-1,3-glucan, which is known to act as a molecular sphincter for PD. Thus, the MP-ANK interaction results in the downregulation of callose and increased cell-to-cell movement of the viral protein. These findings suggest that ANK represents a host cellular receptor exploited by MP to aid viral movement by gating PD through relaxation of their callose sphincters

Heat flux variations beneath central Greenland's ice due to anomalously thin lithosphere

At the Earth’s surface, heat fluxes from the interior1 are generally insignificant compared with those from the Sun and atmosphere2, except in areas permanently blanketed by ice. Modelling studies show that geothermal heat flux influences the internal thermal structure of ice sheets and the distribution of basal melt water3, and it should be taken into account in planning deep ice drilling campaigns and climate reconstructions4. Here we use a coupled ice–lithosphere model driven by climate and show that the oldest and thickest part of the Greenland Ice Sheet is strongly influenced by heat flow from the deep Earth. We find that the geothermal heat flux in central Greenland increases from west to east due to thinning of the lithosphere, which is only about 25–66% as thick as is typical for terrains of early Proterozoic age5. Complex interactions between geothermal heat flow and glaciation-induced thermal perturbations in the upper crust over glacial cycles lead to strong regional variations in basal ice conditions, with areas of rapid basal melting adjoining areas of extremely cold basal ice. Our findings demonstrate the role that the structure of the solid Earth plays in the dynamics of surface processes