Disulfiram Oxy-Derivatives Suppress Protein Retrotranslocation across the ER Membrane to the Cytosol and Initiate Paraptosis-like Cell Death.

Disulfiram (DSF) and its derivatives were here investigated as antineoplastic agents, and their important feature is the ability to influence the UPS. We have recently shown that hydroxocobalamin catalyzes the aerobic oxidation of diethyldithiocarbamate to form disulfiram and its oxy-derivatives (DSFoxy; i.e., sulfones and sulfoxides), which induce cytoplasm vacuolization and paraptosis-like cancer cell death. We used LC-MS/MS and bioinformatics analysis to determine the key points in these processes. DSFoxy was found to induce an increase in the number of ubiquitinated proteins, including oxidized ones, and a decrease in the monomeric ubiquitin. Enhanced ubiquitination was revealed for proteins involved in the response to exogenous stress, regulation of apoptosis, autophagy, DNA damage/repair, transcription and translation, folding and ubiquitination, retrograde transport, the MAPK cascade, and some other functions. The results obtained indicate that DSF oxy-derivatives enhance the oxidation and ubiquitination of many proteins regulating proteostasis (including E3 ligases and deubiquitinases), which leads to inhibition of protein retrotranslocation across the ER membrane into the cytosol and accumulation of misfolded proteins in the ER followed by ER swelling and initiates paraptosis-like cell death. Our results provide new insight into the role of protein ubiquitination/deubiquitination in regulating protein retrotranslocation across the ER membrane into the cytosol and paraptosis-like cell death.

Local Control of Supercurrent Density in Epitaxial Planar Josephson Junctions.

The critical current response to an applied out-of-plane magnetic field in a Josephson junction provides insight into the uniformity of its current distribution. In Josephson junctions with semiconducting weak links, the carrier density, and therefore the overall current distribution, can be modified electrostatically via metallic gates. Here, we show local control of the current distribution in an epitaxial Al-InAs Josephson junction equipped with five minigates. We demonstrate that not only can the junction width be electrostatically defined but also the current profile can be locally adjusted to form superconducting quantum interference devices. Our studies show enhanced edge conduction in such long junctions, which can be eliminated by minigates to create a uniform current distribution.

Demonstration of Protection of a Superconducting Qubit from Energy Decay.

Long-lived transitions occur naturally in atomic systems due to the abundance of selection rules inhibiting spontaneous emission. By contrast, transitions of superconducting artificial atoms typically have large dipoles, and hence their lifetimes are determined by the dissipative environment of a macroscopic electrical circuit. We designed a multilevel fluxonium artificial atom such that the qubit's transition dipole can be exponentially suppressed by flux tuning, while it continues to dispersively interact with a cavity mode by virtual transitions to the noncomputational states. Remarkably, energy decay time T_{1} grew by 2 orders of magnitude, proportionally to the inverse square of the transition dipole, and exceeded the benchmark value of T_{1}>2 ms (quality factor Q_{1}>4×10^{7}) without showing signs of saturation. The dephasing time was limited by the first-order coupling to flux noise to about 4 µs. Our circuit validated the general principle of hardware-level protection against bit-flip errors and can be upgraded to the 0-π circuit [P. Brooks, A. Kitaev, and J. Preskill, Phys. Rev. A 87, 052306 (2013)PLRAAN1050-294710.1103/PhysRevA.87.052306], adding protection against dephasing and certain gate errors.