Characterization of 3 PET tracers for Quantification of Mitochondrial and Synaptic function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J

Mitochondrial complex 1 (MC1) is involved in maintaining brain bioenergetics, the sigma 1 receptor (σ1R) responds to neuronal stress and synaptic vesicle protein 2A (SV2A) reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here we characterise the kinetic behaviour of three positron emission tomography (PET) radioligands 18F-BCPP-EF, 11C-SA-4503 and 11CUCB- J, for the measurement of MC1, σ1R and SV2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans including associated arterial blood sampling with each radioligand. A range of kinetic models were investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All three radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution (VT) were multilinear analysis 1 (MA1) and the 2-tissue compartment (2TC) model for 18F-BCPP-EF, MA1 for 11C-SA- 4503, and both MA1 and the 1-tissue compartment (1TC) model for 11C-UCB-J. Acquisition times of 70, 80 and 60 minutes for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional VT values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases

Switching of Phase-Change Optical Metasurfaces via Remote Thermal Sources

This is the final version.Atomic Weapons Establishment (AWE) plcEngineering and Physical Sciences Research Council (EPSRC

Lens numerical aperture control with phase-change metasurfaces

This is the author accepted manuscript.The control of lens numerical aperture has many applications, including photography, imaging, and laser processing. Here we introduce active control of numerical aperture via a focusing phase-change meta-mirror. This can potentially operate at high speed in a low cost, light and compact format. We demonstrate designs for both infrared (3000 nm) and visible (632.8 nm) wavelengths.Engineering and Physical Sciences Research Council (EPSRC)Atomic Weapons Establishment (AWE

Optical and Thermal Design and Analysis of Phase-Change Metalenses for Active Numerical Aperture Control

This is the final version. Available on open access from MDPI via the DOI in this recordThe control of a lens's numerical aperture has potential applications in areas such as photography and imaging, displays, sensing, laser processing and even laser-implosion fusion. In such fields, the ability to control lens properties dynamically is of much interest, and active meta-lenses of various kinds are under investigation due to their modulation speed and compactness. However, as of yet, meta-lenses that explicitly offer dynamic control of a lens's numerical aperture have received little attention. Here, we design and simulate active meta-lenses (specifically, focusing meta-mirrors) using chalcogenide phase-change materials to provide such control. We show that, operating at a wavelength of 3000 nm, our devices can change the numerical aperture by up to a factor of 1.85 and operate at optical intensities of the order of 1.2 × 109 Wm-2. Furthermore, we show the scalability of our design towards shorter wavelengths (visible spectrum), where we demonstrate a change in NA by a factor of 1.92.Engineering and Physical Sciences Research Council (EPSRC)Margarita Salas fellowshi

Phase-Change Metasurfaces for the Active Control of Lens Numerical Aperture

This is the author accepted manuscript. Available from META Conference via the link in this recordLens numerical aperture (NA) control has applications in many fields, such as photography, imaging, andlaser processing. Active metasurfaces offer the prospect for dynamic control of numerical aperture, in a flat,compact and low-cost format. Here, we design and simulate an active focusing meta-mirror using phase-change materials to provide this control. Designs for use in both the infrared (3000 nm) and visible (632.8nm) are shown.Engineering and Physical Sciences Research Council (EPSRC

Remote Thermal Sources for Switching Phase-Change Material-Based Metasurfaces

This is the final version.Atomic Weapons Establishment (AWE) plcEngineering and Physical Sciences Research Council (EPSRC

Onchocerca parasites and Wolbachia endosymbionts: evaluation of a spectrum of antibiotic types for activity against Onchocerca gutturosa in vitro

BACKGROUND: The filarial parasites of major importance in humans contain the symbiotic bacterium Wolbachia and recent studies have shown that targeting of these bacteria with antibiotics results in a reduction in worm viability, development, embryogenesis, and survival. Doxycycline has been effective in human trials, but there is a need to develop drugs that can be given for shorter periods and to pregnant women and children. The World Health Organisation-approved assay to screen for anti-filarial activity in vitro uses male Onchocerca gutturosa, with effects being determined by worm motility and viability as measured by reduction of MTT to MTT formazan. Here we have used this system to screen antibiotics for anti-filarial activity. In addition we have determined the contribution of Wolbachia depletion to the MTT reduction assay. METHODS: Adult male O. gutturosa were cultured on a monkey kidney cell (LLCMK 2) feeder layer in 24-well plates with antibiotics and antibiotic combinations (6 to 10 worms per group). The macrofilaricide CGP 6140 (Amocarzine) was used as a positive control. Worm viability was assessed by two methods, (i) motility levels and (ii) MTT/formazan colorimetry. Worm motility was scored on a scale of 0 (immotile) to 10 (maximum) every 5 days up to 40 days. On day 40 worm viability was evaluated by MTT/formazan colorimetry, and results were expressed as a mean percentage reduction compared with untreated control values at day 40. To determine the contribution of Wolbachia to the MTT assay, the MTT formazan formation of an insect cell-line (C6/36) with or without insect Wolbachia infection and treated or untreated with tetracycline was compared. RESULTS: Antibiotics with known anti-Wolbachia activity were efficacious in this system. Rifampicin (5 × 10(-5)M) was the most effective anti-mycobacterial agent; clofazimine (1.25 × 10(-5)M and 3.13 × 10(-6)M) produced a gradual reduction in motility and by 40 days had reduced worm viability. The other anti-mycobacterial drugs tested had limited or no activity. Doxycycline (5 × 10(-5)M) was filaricidal, but minocycline was more effective and at a lower concentration (5 × 10(-5)M and 1.25 × 10(-5)M). Inactive compounds included erythromycin, oxytetracycline, trimethoprim and sulphamethoxazole. The MTT assay on the insect cell-line showed that Wolbachia made a significant contribution to the metabolic activity within the cells, which could be reduced when they were exposed to tetracycline. CONCLUSION: The O. gutturosa adult male screen for anti-filarial drug activity is also valid for the screening of antibiotics for anti-Wolbachia activity. In agreement with previous findings, rifampicin and doxycycline were effective; however, the most active antibiotic was minocycline. Wolbachia contributed to the formation of MTT formazan in the MTT assay of viability and is therefore not exclusively a measure of worm viability and indicates that Wolbachia contributes directly to the metabolic activity of the nematode

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: {18}^F-BCPP-EF, {11}^C-SA-4503, and {11}^C-UCB-J

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands—{18}^F-BCPP-EF, {11}^C-SA-4503, and {11}^C-UCB-J for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. METHODS: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. RESULTS: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for {18}^F-BCPP-EF, MA1 for 11}^C-SA-4503, and both MA1 and the 1-tissue-compartment model for {11}^C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on {18}^F-BCPP-EF and {11}^C-UCB-J signal in the caudate. CONCLUSION: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases

X-ray diffraction measurements of plasticity in shock-compressed vanadium in the region of 10-70 GPa

We report experiments in which powder-diffraction data were recorded from polycrystalline vanadium foils, shock-compressed to pressures in the range of 10-70 GPa. Anisotropic strain in the compressed material is inferred from the asymmetry of Debye-Scherrer diffraction images and used to infer residual strain and yield strength (residual von Mises stress) of the vanadium sample material. We find residual anisotropic strain corresponding to yield strength in the range of 1.2 GPa-1.8 GPa for shock pressures below 30 GPa, but significantly less anisotropy of strain in the range of shock pressures above this. This is in contrast to our simulations of the experimental data using a multi-scale crystal plasticity strength model, where a significant yield strength persists up to the highest pressures we access in the experiment. Possible mechanisms that could contribute to the dynamic response of vanadium that we observe for shock pressures ≥30 GPa are discussed