Nuclear Translocation of LDHA Promotes the Catabolism of BCAAs to Sustain GBM Cell Proliferation through the TxN Antioxidant Pathway.

Glutamate is excitotoxic to neurons. The entry of glutamine or glutamate from the blood into the brain is limited. To overcome this, branched-chain amino acids (BCAAs) catabolism replenishes the glutamate in brain cells. Branched-chain amino acid transaminase 1 (BCAT1) activity is silenced by epigenetic methylation in IDH mutant gliomas. However, glioblastomas (GBMs) express wild type IDH. Here, we investigated how oxidative stress promotes BCAAs' metabolism to maintain intracellular redox balance and, consequently, the rapid progression of GBMs. We found that reactive oxygen species (ROS) accumulation promoted the nuclear translocation of lactate dehydrogenase A (LDHA), which triggered DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation and enhanced BCAA catabolism in GBM cells. Glutamate derived from BCAAs catabolism participates in antioxidant thioredoxin (TxN) production. The inhibition of BCAT1 decreased the tumorigenicity of GBM cells in orthotopically transplanted nude mice, and prolonged their survival time. In GBM samples, BCAT1 expression was negatively correlated with the overall survival time (OS) of patients. These findings highlight the role of the non-canonical enzyme activity of LDHA on BCAT1 expression, which links the two major metabolic pathways in GBMs. Glutamate produced by the catabolism of BCAAs was involved in complementary antioxidant TxN synthesis to balance the redox state in tumor cells and promote the progression of GBMs.

Silicon-Based Metastructure Optical Scattering Multiply-Accumulate Computation Chip.

Optical neural networks (ONN) have become the most promising solution to replacing electronic neural networks, which have the advantages of large bandwidth, low energy consumption, strong parallel processing ability, and super high speed. Silicon-based micro-nano integrated photonic platforms have demonstrated good compatibility with complementary metal oxide semiconductor (CMOS) processing. Therefore, without completely changing the existing silicon-based fabrication technology, optoelectronic hybrid devices or all-optical devices of better performance can be achieved on such platforms. To meet the requirements of smaller size and higher integration for silicon photonic computing, the topology of a four-channel coarse wavelength division multiplexer (CWDM) and an optical scattering unit (OSU) are inversely designed and optimized by Lumerical software. Due to the random optical power splitting ratio and incoherency, the intensities of different input signals from CWDM can be weighted and summed directly by the subsequent OSU to accomplish arbitrary multiply-accumulate (MAC) operations, therefore supplying the core foundation for scattering ONN architecture.