Person:

Zhang, Xuan

Background: Mutations in the GCH1 gene are associated with childhood onset, dopa-responsive dystonia (DRD). Correct diagnosis of DRD is crucial, given the potential for complete recovery once treated with L-dopa. The majority of DRD associated mutations lie within the coding region of the GCH1 gene, but three additional single nucleotide sequence substitutions have been reported within the 5’ untranslated (5’UTR) region of the mRNA. The biologic significance of these 5’UTR GCH1 sequence substitutions has not been analyzed. Methodology/Principal Findings Luciferase reporter assays, quantitative real time PCR and RNA decay assays, combined with bioinformatics, revealed a pathogenic 5’UTR GCH1 substitution. The +142C>T single nucleotide 5’UTR substitution that segregates with affected status in DRD patients, substantially attenuates translation without altering RNA expression levels or stability. The +142C>T substitution disrupts translation most likely by creating an upstream initiation start codon (uAUG) and an upstream open reading frame (uORF). Conclusions/Significance: This is the first GCH1 regulatory substitution reported to act at a post-transcriptional level, increasing the list of genetic diseases caused by abnormal translation and reaffirming the importance of investigating potential regulatory substitutions in genetic diseases.

This work presents a switched-capacitor (SC) DC-DC voltage regulator that converts a 3.7V battery voltage down to ~0.8V in order to power the `brain' SoC of a flapping-wing microrobotic bee. A cascade of two 2:1 SC converters offers high efficiency for a 4:1 conversion ratio. A charge recycling technique reduces the flying capacitor's bottom-plate parasitic loss by 50% and overall conversion efficiency reaches 70%. The output droop is less than 10% of the nominal output voltage for a worst-case 47mA load step.

Dystonia is a neurological disorder in which sustained muscle contractions induce twisting and repetitive movements or abnormal posturing. DYT1 early-onset primary dystonia is the most common form of hereditary dystonia and is caused by deletion of a glutamic acid residue (302/303) near the carboxyl-terminus of encoded torsinA. TorsinA is localized primarily within the contiguous lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), and is hypothesized to function as a molecular chaperone and an important regulator of the ER stress-signaling pathway, but how the mutation in torsinA causes disease remains unclear. Multiple lines of evidence suggest that the clinical symptoms of dystonia result from abnormalities in dopamine (DA) signaling, and possibly involving its down-stream effector adenylate cyclase that produces the second messenger cyclic adenosine-3′, 5′-monophosphate (cAMP). Here we find that mutation in torsinA induces ER stress, and inhibits the cyclic adenosine-3′, 5′-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin. Both defective mechanins are corrected by the small molecule 4-phenylbutyrate (4-PBA) that alleviates ER stress. Our results link torsinA, the ER-stress-response, and cAMP-dependent signaling, and suggest 4-PBA could also be used in dystonia treatment. Other pharmacological agents known to modulate the cAMP cascade, and ER stress may also be therapeutic in dystonia patients and can be tested in the models described here, thus supplementing current efforts centered on the dopamine pathway.

We utilize plasma-enhanced chemical vapor deposition through a patterned silica mask for templated diamond growth to create optical resonators. The pyramid-shaped structures have quality factors Q up to 600, measured using confocal photoluminescence spectroscopy, and mode volumes V as small as 2.5(λ/n)32.5(λ/n)3 for resonances at wavelengths λ between 550 and 650 nm, and refractive index n, obtained using finite-difference time-domain simulations. Bright luminescence from nitrogen-vacancy and silicon-vacancy centers in the grown diamond is observed. The resonator design and fabrication technique obviates any etching of diamond, which preserves emitter properties in a pristine host lattice.