Interactions between Magnetic Nanowires and Living Cells : Uptake, Toxicity and Degradation

We report on the uptake, toxicity and degradation of magnetic nanowires by NIH/3T3 mouse fibroblasts. Magnetic nanowires of diameters 200 nm and lengths comprised between 1 {\mu}m and 40 {\mu}m are fabricated by controlled assembly of iron oxide ({\gamma}-Fe2O3) nanoparticles. Using optical and electron microscopy, we show that after 24 h incubation the wires are internalized by the cells and located either in membrane-bound compartments or dispersed in the cytosol. Using fluorescence microscopy, the membrane-bound compartments were identified as late endosomal/lysosomal endosomes labeled with lysosomal associated membrane protein (Lamp1). Toxicity assays evaluating the mitochondrial activity, cell proliferation and production of reactive oxygen species show that the wires do not display acute short-term (< 100 h) toxicity towards the cells. Interestingly, the cells are able to degrade the wires and to transform them into smaller aggregates, even in short time periods (days). This degradation is likely to occur as a consequence of the internal structure of the wires, which is that of a non-covalently bound aggregate. We anticipate that this degradation should prevent long-term asbestos-like toxicity effects related to high aspect ratio morphologies and that these wires represent a promising class of nanomaterials for cell manipulation and microrheology.Comment: 21 pages 12 figure

Advancing human nutrition without degrading land resources through modeling cropping systems in the Ethiopian highlands

Food shortage in sub-Saharan Africa is generally considered a function of limited access to food, with little thought to nutritional quality. Analyzing household production of nutrients across farming systems could be valuable in guiding the improvement of those systems. An optimization model was employed to analyze the scenario of human nutrition and cropland allocation in enset (Enset ventricosum)/root crop-based and cereal-based systems of the Ethiopian Highlands. The type and amount of nutrients produced in each system were analyzed, and an optimization model was used to analyze which cropping strategies might improve the nutritional quality of the household using existing resources. Both production systems were in food deficit, in terms of quantity and quality of nutrients, except for iron. The energy supply of resource-poor households in the enset/root crop-based system was only 75% of the recommended daily dietary allowance (RDA) of the World Health Organization (WHO), whereas resource-rich farmers were able to meet their energy, protein, zinc, and thiamine demands. Extremely high deficiency was found in zinc, calcium, vitamin A, and vitamin C, which provided only 26.5%, 34%, 1.78%, and 12%, of the RDA, respectively. The RDA could be satisfied if the land area occupied by enset, kale, and beans were expanded by about 20%, 10%, and 40%, respectively, at the expense of maize and sweet potato. The cereal-based system also had critical nutrient deficits in calcium, vitamin A, and vitamin C, which provided 30%, 2.5%, and 2% of the RDA, respectively. In the cereal system, the RDA could be fully satisfied by reducing cropland allocated to barley by about 50% and expanding the land area occupied by faba beans, kale, and enset. A shift from the cereal/root crop-dominated system to a perennial-enset dominated system would decrease soil erosion by improving the crop factor by about 45%. This shift would also have a very strong positive impact on soil fertility management. However, any policy suggestions for change in cropland allocation should be done through negotiations with households, communities, and district stakeholders

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML

Clustered Planarity Variants for Level Graphs

We consider variants of the clustered planarity problem for level-planar drawings. So far, only convex clusters have been studied in this setting. We introduce two new variants that both insist on a level-planar drawing of the input graph but relax the requirements on the shape of the clusters. In unrestricted Clustered Level Planarity (uCLP) we only require that they are bounded by simple closed curves that enclose exactly the vertices of the cluster and cross each edge of the graph at most once. The problem y-monotone Clustered Level Planarity (y-CLP) requires that additionally it must be possible to augment each cluster with edges that do not cross the cluster boundaries so that it becomes connected while the graph remains level-planar, thereby mimicking a classic characterization of clustered planarity in the level-planar setting. We give a polynomial-time algorithm for uCLP if the input graph is biconnected and has a single source. By contrast, we show that y-CLP is hard under the same restrictions and it remains NP-hard even if the number of levels is bounded by a constant and there is only a single non-trivial cluster

Fish Oil-Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring

© 2016 Massachusetts Medical Society. Bisgaard, H., Stokholm, J., Chawes, B. L., Vissing, N. H., Bjarnadóttir, E., Schoos, A.-M. M., … Bønnelykke, K. (2016). Fish Oil–Derived Fatty Acids in Pregnancy and Wheeze and Asthma in Offspring. New England Journal of Medicine, 375(26), 2530–2539. https://doi.org/10.1056/NEJMoa1503734BACKGROUND Reduced intake of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) may be a contributing factor to the increasing prevalence of wheezing disorders. We assessed the effect of supplementation with n-3 LCPUFAs in pregnant women on the risk of persistent wheeze and asthma in their offspring. METHODS We randomly assigned 736 pregnant women at 24 weeks of gestation to receive 2.4 g of n-3 LCPUFA (fish oil) or placebo (olive oil) per day. Their children formed the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC 2010) cohort and were followed prospectively with extensive clinical phenotyping. Neither the investigators nor the participants were aware of group assignments during follow-up for the first 3 years of the children's lives, after which there was a 2-year follow-up period during which only the investigators were unaware of group assignments. The primary end point was persistent wheeze or asthma, and the secondary end points included lower respiratory tract infections, asthma exacerbations, eczema, and allergic sensitization. RESULTS A total of 695 children were included in the trial, and 95.5% completed the 3-year, double-blind follow-up period. The risk of persistent wheeze or asthma in the treatment group was 16.9%, versus 23.7% in the control group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.97; P=0.035), corresponding to a relative reduction of 30.7%. Prespecified subgroup analyses suggested that the effect was strongest in the children of women whose blood levels of eicosapentaenoic acid and docosahexaenoic acid were in the lowest third of the trial population at randomization: 17.5% versus 34.1% (hazard ratio, 0.46; 95% CI, 0.25 to 0.83; P=0.011). Analyses of secondary end points showed that supplementation with n-3 LCPUFA was associated with a reduced risk of infections of the lower respiratory tract (31.7% vs. 39.1%; hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.033), but there was no statistically significant association between supplementation and asthma exacerbations, eczema, or allergic sensitization. CONCLUSIONS Supplementation with n-3 LCPUFA in the third trimester of pregnancy reduced the absolute risk of persistent wheeze or asthma and infections of the lower respiratory tract in offspring by approximately 7 percentage points, or one third. (Funded by the Lund-beck Foundation and others; ClinicalTrials.gov number, NCT00798226.)Lundbeck Foundatio