Highlights d The SLC1A5 variant is a mitochondrial glutamine transporter d The SLC1A5 variant has a mitochondrial targeting sequence d Hypoxia controls SLC1A5 variant expression through HIF-2a d The SLC1A5 variant mediates mitochondrial glutamine metabolism in cancer

We extend the Milner-McLeish theory for monodisperse linear polymers to binary blends, where the reptation time of the long chain is set to either the reptation time in the undilated tube or the reptation time in the dilated tube depending on the value of the "Graessley parameter" Gr ≡ M2Me 2 /M1 3 , where M1 is the short chain molecular weight, M2 is the long chain molecular weight, and Me is the entanglement molecular weight. We find experimentally that, in blends in which Gr is much smaller than the critical value Grc ≈ 0.064 established by an observed crossover in diffusivity measurements [Green et al. Phys. Rev. Lett. 1984, 26, 2145, the long-chain motion in the binary blend is well predicted by the Milner-McLeish model using reptation in the undilated tube. However, for Gr larger than Grc, reptation must to be assumed to occur in a dilated tube to obtain agreement with the experimental data. These results confirm that the crossover behavior observed in diffusivity also occurs in rheology and show that existing tube models can accurately predict linear rheology in both regimes where reptation occurs in a dilated or an undilated tube.

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Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity. For further analysis, we selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity. It also effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations.