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.     

Effects of upholstery materials on the burning behavior of real‐scale residential upholstered furniture mock‐ups

Fire spread and growth on real‐scale four cushion mock‐ups of residential upholstered furniture (RUF) were investigated with the goal of identifying whether changes in five classes of materials (barrier, flexible polyurethane foam, polyester fiber wrap, upholstery fabric, and sewing thread), referred to as factors, resulted in statistically significant changes in burning behavior. A fractional factorial experimental design plus practical considerations yielded a test matrix with 20 material combinations. Experiments were repeated a minimum of two times. Measurements included fire spread rates derived from video recordings and heat release rates (HRRs). A total of 13 experimental parameters (3 based on the videos and 10 on the HRR results), referred to as responses, characterized the measurements. Statistical analyses based on Main Effects Plots (main effects) and Block Plots (main effects and factor interactions) were used. The results showed that three of the factors resulted in statistically significant effects on varying numbers of the 13 responses. The Barrier and Fabric factors had the strongest main effects with roughly comparable magnitudes. Foam was statistically significant for fewer of the responses and its overall strength was weaker than for Barrier and Fabric. No statistically significant main effects were identified for Wrap or Thread. Multiple two‐term interactions between factors were identified as being statistically significant. The Barrier*Fabric interaction resulted in the highest number of and strongest statistically significant effects. The existence of two‐term interactions means that it will be necessary to consider their effects in approaches designed to predict the burning behavior of RUF.     

Environmental effects on the strength and impact damage resistance of alumina based oxide/oxide ceramic matrix composites

In this study the effects of high temperature and moisture on the impact damage resistance and mechanical strength of Nextel 610/alumina silicate ceramic matrix composites were experimentally evaluated. Composite laminates were exposed to either a 1050°C isothermal furnace-based environment for 30 consecutive days at 6 h a day, or 95% relative humidity environment for 13 consecutive days at 67°C. Low velocity impact, tensile and short beam strength tests were performed on both ambient and environmentally conditioned laminates and damage was characterized using a combination of non-destructive and destructive techniques. High temperature and humidity environmental exposure adversely affected the impact resistance of the composite laminates. For all the environments, planar internal damage area was greater than the back side dent area, which in turn was greater than the impactor side dent area. Evidence of environmental embrittlement through a stiffer tensile response was noted for the high temperature exposed laminates while the short beam strength tests showed greater propensity for interlaminar shear failure in the moisture exposed laminates. Destructive evaluations exposed larger, more pronounced delaminations in the environmentally conditioned laminates in comparison to the ambient ones. External damage metrics of the impactor side dent depth and area directly influenced the post-impact tensile strength of the laminates while no such trend between internal damage area and residual strength could be ascertained.     

The control of sea lice in Atlantic salmon by selective breeding

Sea lice threaten the welfare of farmed Atlantic salmon and the sustainability of fish farming across the world. Chemical treatments are the major method of control but drug resistance means that alternatives are urgently needed. Selective breeding can be a cheap and effective alternative. Here, we combine experimental trials and diagnostics to provide a practical protocol for quantifying resistance to sea lice. We then combined quantitative genetics with epidemiological modelling to make the first prediction of the response to selection, quantified in terms of reduced need for chemical treatments. We infected over 1400 young fish with Lepeophtheirus salmonis, the most important species in the Northern Hemisphere. Mechanisms of resistance were expressed early in infection. Consequently, the number of lice per fish and the ranking of families were very similar at 7 and 17 days post infection, providing a stable window for assessing susceptibility to infection. The heritability of lice numbers within this time window was moderately high at 0.3, confirming that selective breeding is viable. We combined an epidemiological model of sea lice infection and control on a salmon farm with genetic variation in susceptibility among individuals. We simulated 10 generations of selective breeding and examined the frequency of treatments needed to control infection. Our model predicted that substantially fewer chemical treatments are needed to control lice outbreaks in selected populations and chemical treatment could be unnecessary after 10 generations of selection. Selective breeding for sea lice resistance should reduce the impact of sea lice on fish health and thus substantially improve the sustainability of Atlantic salmon production.     

Measurement of Electrophysiological Signals In Vitro Using High-Performance Organic Electrochemical Transistors

Biological environments use ions in charge transport for information transmission. The properties of mixed electronic and ionic conductivity in organic materials make them ideal candidates to transduce physiological information into electronically processable signals. A device proven to be highly successful in measuring such information is the organic electrochemical transistor (OECT). Previous electrophysiological measurements performed using OECTs show superior signal-to-noise ratios than electrodes at low frequencies. Subsequent development has significantly improved critical performance parameters such as transconductance and response time. Here, interdigitated-electrode OECTs are fabricated on flexible substrates, with one such state-of-the-art device achieving a peak transconductance of 139 mS with a 138 µs response time. The devices are implemented into an array with interconnects suitable for micro-electrocorticographic application and eight architecture variations are compared. The two best-performing arrays are subject to the full electrophysiological spectrum using prerecorded signals. With frequency filtering, kHz-scale frequencies with 10 µV-scale voltages are resolved. This is supported by a novel quantification of the noise, which compares the gate voltage input and drain current output. These results demonstrate that high-performance OECTs can resolve the full electrophysiological spectrum and suggest that superior signal-to-noise ratios could be achieved in high frequency measurements of multiunit activity.