Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy. rapamycin treatment. Activation of mTORC1 by growth factors and nutrientsThe activation of mTORC1 is dependent on nutrients and growth factors. In response to nutrients, mTORC1 translocates from the cytoplasm to the lysosomal surface, where it is activated by growth factors via PI3K-AKT signalling. Growth factors, for instance, insulin, activate AKT4 via a cognate receptor, phosphoinositide-dependent kinase 1 (PDK1) and PI3K (Fig. 1). AKT inhibits the TSC1-TSC2 complex5, which is a GTPase-activating protein (GAP) for the small GTPase RHEB6. GTP-bound RHEB directly binds and activates mTORC1 at the lysosome 7,8 (Fig. 1). Nutrient-induced lysosomal translocation of mTORC1Nutrients, in particular amino acids, promote lysosomal localization of mTORC1 via the RAS-related GTP-binding proteins (RAGs) 9 , thereby enabling mTORC1 to encounter RHEB. RAGs are small GTPases that form obligate heterodimers. RAGA or RAGB associates with RAGC or RAGD. In the active state, GTP-bound RAGA or RAGB and GDP-bound RAGC or RAGD bind RAPTOR and thereby recruit mTORC1 to the lysosomal surface. The nucleotide binding status of the RAGs is tightly regulated by amino acids 9 obtained from intracellular synthesis, protein turnover or extracellular sources via specific transporters (Fig. 1; for details, see following sections). Among the amino acids, leucine, arginine and glutamine are the most effective activators of mTORC1. Leucine and arginine bind to sestrin 2 and CASTOR1, respectively, ultimately to activate the RAGs and mTORC1 (for details, see Fig. 1, ref. 10 and references therein). The lysosomal amino acid transporter SLC38A9 promotes mTORC1 activation by exporting essential amino acids to the cytoplasm 11 , where, for example, leucine can bind sestrin 2. Leucine export is stimulated by arginine binding to SLC38A9 (ref. 11 ). Glutamine activates RAGs by promoting glutaminolysis. During glutaminolysis, glutaminase (GLS) and glutamate dehydrogenase (GDH) convert glutamine to αketoglutarate (αKG), which ultimately activates mTORC1 via prolyl hydroxylases (PHDs) by promoting GTP loading of RAGB12 (Fig. 1). Leucine also stimulates αKG production by directly binding and allosterically activating GDH. Furthermore, glutamine activates mTORC1 independently of RAGs via the small GTPase ADPri...

The signalling lipid PI(3,5)P 2 is generated on endosomes and regulates retrograde traffic to the trans-Golgi network. Physiological signals regulate rapid, transient changes in PI(3,5)P 2 levels. Mutations that lower PI(3,5)P 2 cause neurodegeneration in human patients and mice. The function of Vac14 in the regulation of PI(3,5)P 2 was uncharacterized previously. Here, we predict that yeast and mammalian Vac14 are composed entirely of HEAT repeats and demonstrate that Vac14 exerts an effect as a scaffold for the PI(3,5)P 2 regulatory complex by direct contact with the known regulators of PI(3,5)P 2 : Fig4, Fab1, Vac7 and Atg18. We also report that the mouse mutant ingls (infantile gliosis) results from a missense mutation in Vac14 that prevents the association of Vac14 with Fab1, generating a partial complex. Analysis of ingls and two additional mutants provides insight into the organization of the PI(3,5)P 2 regulatory complex and indicates that Vac14 mediates three distinct mechanisms for the rapid interconversion of PI3P and PI(3,5)P 2 . Moreover, these studies show that the association of Fab1 with the complex is essential for viability in the mouse.

Most of touchable surfaces in MERS units were contaminated by patients and health care workers and the viable virus could shed through respiratory secretion from clinically fully recovered patients. These results emphasize the need for strict environmental surface hygiene practices, and sufficient isolation period based on laboratory results rather than solely on clinical symptoms.

Highly efficient and bendable organic solar cells (OSCs) are fabricated using solution‐processed silver nanowire (Ag NW) electrodes. The Ag NW films were highly transparent (diffusive transmittance ≈ 95% at a wavelength of 550 nm), highly conductive (sheet resistance ≈ 10 Ω sq−1), and highly flexible (change in resistance ≈ 1.1 ± 1% at a bending radius of ≈200 μm). Power conversion efficiencies of ≈5.80 and 5.02% were obtained for devices fabricated on Ag NWs/glass and Ag NWs/poly(ethylene terephthalate) (PET), respectively. Moreover, the bendable devices fabricated using the Ag NWs/PET films decrease slightly in their efficiency (to ≈96% of the initial value) even after the devices had been bent 1000 times with a radius of ≈1.5 mm.