Pharmacokinetics of Quinacrine Efflux from Mouse Brain via the P-glycoprotein Efflux Transporter

The lipophilic cationic compound quinacrine has been used as an antimalarial drug for over 75 years but its pharmacokinetic profile is limited. Here, we report on the pharmacokinetic properties of quinacrine in mice. Following an oral dose of 40 mg/kg/day for 30 days, quinacrine concentration in the brain of wild-type mice was maintained at a concentration of ∼1 µM. As a substrate of the P-glycoprotein (P-gp) efflux transporter, quinacrine is actively exported from the brain, preventing its accumulation to levels that may show efficacy in some disease models. In the brains of P-gp–deficient Mdr10/0 mice, we found quinacrine reached concentrations of ∼80 µM without any signs of acute toxicity. Additionally, we examined the distribution and metabolism of quinacrine in the wild-type and Mdr10/0 brains. In wild-type mice, the co-administration of cyclosporin A, a known P-gp inhibitor, resulted in a 6-fold increase in the accumulation of quinacrine in the brain. Our findings argue that the inhibition of the P-gp efflux transporter should improve the poor pharmacokinetic properties of quinacrine in the CNS

High refresh rate three dimensional positioning system using frequency-multiplexed electromagnetic fields

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Durham adaptive optics real-time controller

The Durham adaptive optics (AO) real-time controller was initially a proof of concept design for a generic AO control system. It has since been developed into a modern and powerful central-processing-unit-based real-time control system, capable of using hardware acceleration (including field programmable gate arrays and graphical processing units), based primarily around commercial off-the-shelf hardware. It is powerful enough to be used as the real-time controller for all currently planned 8 m class telescope AO systems. Here we give details of this controller and the concepts behind it, and report on performance, including latency and jitter, which is less than 10 μs for small AO systems

Non-deep physiological dormancy and germination characteristics of Primula florindae (Primulaceae), a rare alpine plant in the Hengduan Mountains of southwest China

Timing of seed germination is directly related to the survival probability of seedlings. For alpine plants, autumn-dispersal seeds should not germinate immediately because the cold temperature is not conducive to the survival of seedlings. Seed dormancy is a characteristic of the seed that prevents it from germinating after dispersal. Primula florindae is an alpine perennial forb endemic to eastern Tibet, SW China. We hypothesized that primary dormancy and environmental factors prevent seeds of P. florindae to germinate in autumn and allow them to germinate at the first opportunity in spring. We determined how GA3, light, temperature, dry after-ripening (DAR) and cold-wet stratification (CS) treatments affect seed germination by conducting a series of laboratory experiments. Firstly, the effects of gibberellic acid (GA3; 0, 20, and 200 mg L−1) on germination of freshly shed seeds at alternating temperatures (15/5 and 25/15 °C) were immediately investigated to characterize seed with a physiological dormancy component. Then, the fresh seeds treated with 0, 3, and 6 months of after-ripening (DAR) and cold-wet stratification (CS) were incubated at seven constant (1, 5, 10, 15, 20, 25, and 30 °C) and two alternating temperatures (5/1, 15/5, and 25/15 °C) at light and dark conditions. Fresh seeds were dormant, which only germinated well (>60%) at 20, 25, and 25/15 °C in light but not at ≤15 °C and to higher percentages in light than in dark. GA3 increased germination percentage of fresh seeds, and DAR or CS treatments increased final germination percentage, germination rate (speed), and widened the temperature range for germination from high to low. Moreover, CS treatments reduced the light requirement for germination. Thus, after dormancy release, seeds germinated over a wide range of constant and alternating temperatures, regardless of light conditions. Our results demonstrated that P. florindae seeds have type 2 non-deep physiological dormancy. Timing of germination should be restricted to early spring, ensuring a sufficient length of the growing season for seedling recruitment. These dormancy/germination characteristics prevent seeds from germinating in autumn when temperatures are low but allow them to germinate after snowmelt in spring

Shack-Hartmann sensor improvement using optical binning

We present a design improvement for a recently proposed type of Shack-Hartmann wavefront sensor that uses a cylindrical (lenticular) lenslet array. The improved sensor design uses optical binning and requires significantly fewer detector pixels than the corresponding conventional or cylindrical Shack-Hartmann sensor, and so detector readout noise causes less signal degradation. Additionally, detector readout time is significantly reduced, which reduces the latency for closed loop systems, and data processing requirements. We provide simple analytical noise considerations and Monte-Carlo simulations, and show that the optically binned Shack-Hartmann sensor can offer better performance than the conventional counterpart in most practical situations, and our design is particularly suited for use with astronomical adaptive optics systems.Comment: Accepted for publication in Applied Optic

A novel sterol regulatory element-binding protein gene (sreA) identified in penicillium digitatum is required for prochloraz resistance, full virulence and erg11 (cyp51) regulation.

Penicillium digitatum is the most destructive postharvest pathogen of citrus fruits, causing fruit decay and economic loss. Additionally, control of the disease is further complicated by the emergence of drug-resistant strains due to the extensive use of triazole antifungal drugs. In this work, an orthologus gene encoding a putative sterol regulatory element-binding protein (SREBP) was identified in the genome of P. digitatum and named sreA. The putative SreA protein contains a conserved domain of unknown function (DUF2014) at its carboxyl terminus and a helix-loop-helix (HLH) leucine zipper DNA binding domain at its amino terminus, domains that are functionally associated with SREBP transcription factors. The deletion of sreA (ΔsreA) in a prochloraz-resistant strain (PdHS-F6) by Agrobacterium tumefaciens-mediated transformation led to increased susceptibility to prochloraz and a significantly lower EC50 value compared with the HS-F6 wild-type or complementation strain (COsreA). A virulence assay showed that the ΔsreA strain was defective in virulence towards citrus fruits, while the complementation of sreA could restore the virulence to a large extent. Further analysis by quantitative real-time PCR demonstrated that prochloraz-induced expression of cyp51A and cyp51B in PdHS-F6 was completely abolished in the ΔsreA strain. These results demonstrate that sreA is a critical transcription factor gene required for prochloraz resistance and full virulence in P. digitatum and is involved in the regulation of cyp51 expression