Objective The lesions of Parkinson's disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded α-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous α-synuclein to misfold. Here, we characterized and quantified the axonal transport of α-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport. Methods We grew primary cortical mouse neurons in microfluidic devices to separate soma from axonal projections in fluidically isolated microenvironments. We used live-cell imaging and immunofluorescence to characterize the transport of fluorescent α-synuclein fibrils and their transfer to second-order neurons. Results Fibrillar α-synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component-b of axonal transport (fast axonal transport with saltatory movement). Fibrillar α-synuclein was readily observed in the cell bodies of second-order neurons following anterograde axonal transport. Axon-to-soma transfer appeared not to require synaptic contacts. Interpretation These results support the hypothesis that the progression of Parkinson's disease can be caused by neuron-to-neuron spread of α-synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be transsynaptic gives hope that α-synuclein fibrils could be intercepted by drugs during the extra-cellular phase of their journey.

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Since the etiology of vitiligo is still unknown, we searched for some abnormal biochemical parameters, if any, in subjects with vitiligo. Higher urinary excretion of indole metabolites in vitiliginous patients have been noted, in association with higher dioxygenase, superoxide dismutase, and tyrosine aminotransferase activity in their serum. Similar results have also been found in an animal model, Bufo melanostictus, during induced tyrosinase inhibition. Treatment with psoralen can reverse the parameters, except tyrosine aminotransferase, to a normal level. Although psoralens are not the magic bullet for the therapy of vitiligo, they are still being used as a chemotherapeutic agent against vitiligo on a major scale to date. Tryptophan was found to participate in the pathway of melanogenesis, as a precursor as well as a positive regulator of tyrosinase. Its behavior in this regard is much more similar to the conventional substrates tyrosine and dopa (dihydroxyphenylalanine). In consideration of combined participation of tyrosine and tryptophan in the synthesis of melanin and its breakdown, the possible influence of different enzymatic reactions, like mono-oxygenase, dioxygenase, and deamination, has been suggested.

We report on the electrically driven rotation of 2.4-µm-radius, optically levitated dielectric microspheres. Electric fields are used to apply torques to a microsphere's permanent electric dipole moment, while angular displacement is measured by detecting the change in polarization state of light transmitted through the microsphere (MS). This technique enables greater control than previously achieved with purely optical means because the direction and magnitude of the electric torque can be set arbitrarily. We measure the spin-down of a microsphere released from a rotating electric field, the harmonic motion of the dipole relative to the instantaneous direction of the field, and the phase lag between the driving electric field and the dipole moment of the MS due to drag from residual gas. We also observe the gyroscopic precession of the MS when the axis of rotation of the driving field and the angular momentum of the microsphere are orthogonal. These observations are in quantitative agreement with the equation of motion. The control offered by the electrical drive enables precise measurements of microsphere properties and torque as well as a method for addressing the direction of angular momentum for an optically levitated particle. arXiv:1812.09625v3 [physics.optics]

We report on the use of 4.7-µm-diameter, optically levitated, charged microspheres to image the three-dimensional force field produced by charge distributions on an Au-coated, microfabricated Si beam in vacuum. An upward-propagating, single-beam optical trap, combined with an interferometric imaging technique, provides optimal access to the microspheres for microscopy. In this demonstration, the Au-coated surface of the Si beam can be brought as close as ∼10 µm from the center of the microsphere while forces are simultaneously measured along all three orthogonal axes, fully mapping the vector force field over a total volume of ∼10 6 µm 3 . We report a force sensitivity of (2.5 ± 1.0) × 10 −17 N/ √ Hz, in each of the three degrees of freedom, with a linear response to up to ∼10 −13 N. While we discuss the case of mapping static electric fields using charged microspheres, it is expected that the technique can be extended to other force fields, using microspheres with different properties.

The solution phase synthesis of a 167-member library of isocoumarins is described. The key intermediates for library generation, 4-iodoisocoumarins, are easily prepared by iodocyclization of the corresponding 2-(1-alkynyl)arenecarboxylate esters. The 4-iodoisocoumarins undergo palladium-catalyzed Sonogashira, Suzuki-Miyura and Heck reactions to yield a diverse set of isocoumarins. Alternatively, isocoumarins, bearing hydroxyl or bromine functionalities, have been prepared by ZnCl2 and Pd(PPh3)4 mediated cyclization of the corresponding o-iodobenzoic acid and appropriate terminal alkynes. The resulting isocoumarins were further diversified by derivatization of the hydroxyl or bromine groups. A small set of isoquinolinones were also prepared from the corresponding isocoumarins.