Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.     

Consistent Viewing and Interaction for Multiple Users in Projection-Based VR Systems

In projection-based Virtual Reality (VR) systems, typically only one headtracked user views stereo images rendered from the correct view position. For other users, who are presented a distorted image, moving with the first user's head motion, it is difficult to correctly view and interact with 3D objects in the virtual environment. In close-range VR systems, such as the Virtual Workbench, distortion effects are especially large because objects are within close range and users are relatively far apart. On these systems, multi-user collaboration proves to be difficult. In this paper, we analyze the problem and describe a novel, easy to implement method to prevent and reduce image distortion and its negative effects on close-range interaction task performance. First, our method combines a shared camera model and view distortion compensation. It minimizes the overall distortion for each user, while important user-personal objects such as interaction cursors, rays and controls remain distortion-free. Second, our method retains co-location for interaction techniques to make interaction more consistent. We performed a user experiment on our Virtual Workbench to analyze user performance under distorted view conditions with and without the use of our method. Our findings demonstrate the negative impact of view distortion on task performance and the positive effect our method introduces. This indicates that our method can enhance the multi-user collaboration experience on close-range, projection-based VR systems.     

The anaerobic oxidation of hydrazine: a novel reaction in microbial nitrogen metabolism

PURPOSE: Pulmonary involvement (PI) is common in leptospiral infection, usually characterized by hemoptysis and diffuse bilateral infiltrates on chest radiographs. Alveolar haemorrhage (AH) has already been proved by autopsy and some case-reports with fiberoptic bronchoscopy (FB) and bronchoalveolar lavage (BAL). The purpose of this study was 1/to evaluate the incidence of AH in leptospirosis 2/to define the impact of BAL on the early diagnosis of the infection. PATIENTS AND METHODS: FB with BAL were performed in 23 consecutive patients with leptospirosis (13 patients with patent signs of PI: group 1, 10 patients without: group 2). AH was defined by a percentage of siderophages > or = 20% and/or a Golde score > 100 and/or an haemorrhagic aspect of BAL fluid. Culture tests were performed on specific medium. RESULTS: We diagnosed AH in all patients of group 1 and in 7 patients of group 2. Filaments were seen in 6 specimens of BAL fluid, initially thought to be leptospires, but culture tests were negative. CONCLUSION: AH is identified in all cases of leptospirosis with PI. Occult AH often occurs to patients without any respiratory symptom. Physicians should consider leptospiral infection in the differential diagnosis of AH. Culture-tests for leptospirosis in BAL do no help in diagnosing leptospirosis.     

The Esterase PfeE,the Achilles’ Heel in the Battle for Iron between Pseudomonas aeruginosa and Escherichia coli

Bacteria access iron, a key nutrient, by producing siderophores or using siderophores produced by other microorganisms. The pathogen Pseudomonas aeruginosa produces two siderophores but is also able to pirate enterobactin (ENT), the siderophore produced by Escherichia coli. ENT-Fe complexes are imported across the outer membrane of P. aeruginosa by the two outer membrane transporters PfeA and PirA. Iron is released from ENT in the P. aeruginosa periplasm by hydrolysis of ENT by the esterase PfeE. We show here that pfeE gene deletion renders P. aeruginosa unable to grow in the presence of ENT because it is unable to access iron via this siderophore. Two-species co-cultures under iron-restricted conditions show that P. aeruginosa strongly represses the growth of E. coli as long it is able to produce its own siderophores. Both strains are present in similar proportions in the culture as long as the siderophore-deficient P. aeruginosa strain is able to use ENT produced by E. coli to access iron. If pfeE is deleted, E. coli has the upper hand in the culture and P. aeruginosa growth is repressed. Overall, these data show that PfeE is the Achilles’ heel of P. aeruginosa in communities with bacteria producing ENT.     

An augmented Lagrangian approach to non-convex SAO using diagonal quadratic approximations

Successful gradient-based sequential approximate optimization (SAO) algorithms in simulation-based optimization typically use convex separable approximations. Convex approximations may however not be very efficient if the true objective function and/or the constraints are concave. Using diagonal quadratic approximations, we show that non-convex approximations may indeed require significantly fewer iterations than their convex counterparts. The nonconvex subproblems are solved using an augmented Lagrangian (AL) strategy, rather than the Falk-dual, which is the norm in SAO based on convex subproblems. The results suggest that transformation of large-scale optimization problems with only a few constraints to a dual form via convexification need sometimes not be required, since this may equally well be done using an AL formulation.     

An assessment of the ability of computational fluid dynamic models to predict reactive gas–solid flows in a fluidized bed

Fine grid, two dimensional simulations of reactive gas–solid flows occurring in a fluidized bed reactor were carried out using the Eulerian multi-fluid kinetic theory of granular flow (KTGF) approach in the commercial flow solver, ANSYS FLUENT 12.1. The fuel reactor of a pilot scale Chemical Looping Combustion rig, operated in the bubbling fluidization regime at the Vienna University of Technology, was simulated. Grid dependence studies were carried out as well as sensitivity studies to the fuel inlet condition and the inclusion of gas phase turbulence. Simulations could not accurately reproduce the experimental trend for the case when highly reactive nickel oxide was used as the oxygen carrier material, but in general satisfactory quantitative agreement was observed. The failure to correctly capture the experimental trend was primarily attributed to the fine length-scales at the feed gas inlets not being adequately resolved even at the finest grid investigated. The trend quickly worsened when coarser grids were used, indicating that the generality of the model is lost when grid dependence effects are present. A number of possible dimensional effects were also discussed. Subsequently, the model was used to successfully capture another experimental trend obtained with a much less reactive ilmenite oxygen carrier material. The model captured this trend correctly because the reaction was now limited by the reaction rate and not by species transfer to the large scale gas-emulsion interfaces. Results were therefore not as sensitive to the correct hydrodynamic modelling of the interface, especially near the gas inlets, and the model retained its generality over a wide range of operating conditions.     

Mechanical properties of morcellised bone graft with the addition of hydroxyapatite

Mixtures of morcellised bone graft (MBG) and hydroxyapatite (HA) are frequently used in revision arthroplasty surgery. However, the changes in the mechanical properties from adding HA to MBG are unknown. This study used a uniaxial compression test to replicate impaction bone grafting and subsequent early postoperative weightbearing to investigate the effect of adding different proportion of HA to MBG. To achieve this aim, human MBG was subjected to increasing impaction forces and the apparent stiffness and creep for each stress level determined. Subsequently, increasing proportions porous and non porous HA were added to the MBG. The major findings were that the apparent stiffness for MBG increased and the associated creep decreased both with the application of increasing stress and with the addition of increasing proportions of HA. In conclusion, greater proportions of HA in the graft mixture improved the mechanical response compared with MBG impacted under the same force. This improvement replicated the properties of pure MBG under high axial stress. This study indicates that graft mixtures of MBG and HA can be tailormade for patients. The need for less impaction force in MBG:HA mixtures to obtain the same properties as pure MBG may decrease the risk of intraoperative fracture.     

Polymer‐based transistors used as pixel switches in active‐matrix displays

A 2‐in. active‐matrix display was demonstrated, containing 4096 solution‐processed polymer‐based transistors. By using the polymer‐dispersed liquid‐crystal display (LCD) effect, this results in a reflective, low‐power display with paper‐like contrast. The influence of the transistor parameters on the display performance is analyzed by use of a model for charging and discharging of the pixel capacitors. Good agreement was obtained between the model and the experimental data. Scaling behavior allows estimation of the performance required for transistors in a quarter‐VGA display. These requirements are met by solution‐processed pentacene transistors.