Glycolysis maintains AMPK activation in sorafenib-induced Warburg effect.

Hepatocellular carcinoma (HCC) is the second deadly cancer in the world and still lacks curative treatment. Aerobic glycolysis, or Warburg effect, is a major resistance mechanism induced by first-line treatment of HCC, sorafenib, and is regulated by the master regulator of metabolism, AMPK. Activation of AMPK is required for resistance; however, activation dynamics of AMPK and its regulation is rarely studied. Engineering cells to express an AMPK activity biosensor, we monitor AMPK activation in single HCC cells in a high throughput manner during sorafenib-induced drug resistance. Sorafenib induces transient activation of AMPK, duration of which is dependent on glucose. Inhibiting glycolysis shortens AMPK activation; whereas increasing glycolysis increases its activation duration. Our data highlight that activation duration of AMPK is important for cancer evasion of therapeutic treatment and glycolysis is a key regulator of activation duration of AMPK.

Plasma Oxidation of Copper: Molecular Dynamics Study with Neural Network Potentials.

The formation of thin oxide films is of significant scientific and practical interest. In particular, the semiconductor industry is interested in developing a plasma atomic layer etching process to pattern copper, replacing the dual Damascene process. Using a nonthermal oxygen plasma to convert the metallic copper into copper oxide, followed by a formic acid organometallic reaction to etch the copper oxide, this process has shown great promise. However, the current process is not optimal because the plasma oxidation step is not self-limiting, hampering the degree of thickness control. In the present study, a neural network potential for the binary interaction between copper and oxygen is developed and validated against first-principles calculations. This potential covers the entire range of potential energy surfaces of metallic copper, copper oxides, atomic oxygen, and molecular oxygen. The usable kinetic energy ranges from 0 to 20 eV. Using this potential, the plasma oxidation of copper surfaces was studied with large-scale molecular dynamics at atomic resolution, with an accuracy approaching that of the first principle calculations. An amorphous layer of CuO is formed on Cu, with thicknesses reaching 2.5 nm. Plasma is found to create an intense local heating effect that rapidly dissipates across the thickness of the film. The range of this heating effect depends on the kinetic energy of the ions. A higher ion energy leads to a longer range, which sustains faster-than-thermal rates for longer periods of time for the oxide growth. Beyond the range of this agitation, the growth is expected to be limited to the thermally activated rate. High-frequency, repeated ion impacts result in a microannealing effect that leads to a quasicrystalline oxide beneath the amorphized layer. The crystalline layer slows down oxide growth. Growth rate is fitted to the temperature gradient due to ion-induced thermal agitations, to obtain an apparent activation energy of 1.0 eV. A strategy of lowering the substrate temperature and increasing plasma power is proposed as being favorable for more self-limited oxidation.