Monitoring the dynamics of Src activity in response to anti-invasive dasatinib treatment at a subcellular level using dual intravital imaging

Optimising response to tyrosine kinase inhibitors in cancer remains an extensive field of research. Intravital imaging is an emerging tool, which can be used in drug discovery to facilitate and fine-tune maximum drug response in live tumors. A greater understanding of intratumoural delivery and pharmacodynamics of a drug can be obtained by imaging drug target-specific fluorescence resonance energy transfer (FRET) biosensors in real time. Here, we outline our recent work using a Src-FRET biosensor as a readout of Src activity to gauge optimal tyrosine kinase inhibition in response to dasatinib treatment regimens in vivo. By simultaneously monitoring both the inhibition of Src using FRET imaging, and the modulation of the surrounding extracellular matrix using second harmonic generation (SHG) imaging, we were able to show enhanced drug penetrance and delivery to live pancreatic tumors. We discuss the implications of this dual intravital imaging approach in the context of altered tumor-stromal interactions, while summarising how this approach could be applied to assess other combination strategies or tyrosine kinase inhibitors in a preclinical setting

Gas to liquid mass transfer in rheologically complex fluids

The increase of studies relaying on gas to liquid mass transfer in digested sludge (shear thinning fluid) necessitates a better understanding of the impact of apparent viscosity (μa) and rheology in process performance. Mass transfer retardation due to μa variations was investigated in a pilot scale absorption bubble column for Newtonian and shear thinning fluids with varied superficial gas velocities (UG). A non-linear reduction of mass transfer efficiency with increasing μa was observed, being the impact higher at low μa ranges and high UG. An increase of 114 cPo in μ from 1.01 to 115 cPo in glycerol solutions saturated with UG = 1.73 cm s−1 led to a reduction of 96% in kLa (α = 0.04), while a comparable raise from 115 to 229 cPo implied a reduction of 52% (α = 0.02). Slug–annular flow regime was identified for shear thinning fluids of high μa (1.0% and 1.5% carboxymethyl cellulose sodium salt solutions), where bubble buoyancy was conditioned by the μ of the fluid at rest and the active volume for mass transfer was reduced because of the presence of stagnant areas. Conditions imitating the rheological variability of anaerobically digested sewage sludge were included within those tested, being a reduction in gas transfer efficiency of 6 percentage points (from 7.6 ± 0.3% to 1.6 ± 0.1%) recorded when increasing μa from 130 to 340 cPo. It is thus recommended that rheology and μa variability are accounted for within the design of gas to liquid mass transfer systems involving digested sewage sludge, in order to avoid reductions in process performance and active volume

Quantifying physiological influences on otolith microchemistry

Trace element concentrations in fish earstones (‘otoliths’) are widely used to discriminate spatially discrete populations or individuals of marine fish, based on a commonly held assumption that physiological influences on otolith composition are minor, and thus variations in otolith elemental chemistry primarily reflect changes in ambient water chemistry. We carried out a long-term (1-year) experiment, serially sampling seawater, blood plasma and otoliths of mature and immature European plaice (Pleuronectes platessa L.) to test relationships between otolith chemistry and environmental and physiological variables. Seasonal variations in otolith elemental composition did not track seawater concentrations, but instead reflected physiological controls on metal transport and biokinetics, which are likely moderated by ambient temperature. The influence of physiological factors on otolith composition was particularly evident in Sr/Ca ratios, the most widely used elemental marker in applied otolith microchemistry studies. Reproduction also triggered specific variations in otolith and blood plasma metal chemistry, especially Zn/Ca ratios in female fish, which could potentially serve as retrospective spawning indicators. The influence of physiology on the trace metal composition of otoliths may explain the success of microchemical stock discrimination in relatively homogenous marine environments, but could complicate alternative uses for trace element compositions in biominerals of higher organism

Inverse scaling trends for charge-trapping-induced degradation of FinFETs performance

In this paper, we investigate the impact of a single discrete charge trapped at the top oxide interface on the performance of scaled nMOS FinFET transistors. The charge-trapping-induced gate voltage shift is simulated as a function of the device scaling and for several regimes of conduction-from subthreshold to ON-state. Contrary to what is expected for planar MOSFETs, we show that the trap impact decreases with scaling down the FinFET size and the applied gate voltage. By comparing drift-diffusion with nonequilibrium Green functions simulations, we show that quantum effects in the charge distribution and transport can reduce or amplify the impact of discrete traps in simulation of reliability resilience of scaled FinFETs