Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm -deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.

Peroxisomes are highly metabolic, autonomously replicating organelles that generate ROS as a by product of fatty acid β-oxidation. Consequently, cells must maintain peroxisome homeostasis, or risk pathologies associated with too few peroxisomes, such as peroxisome biogenesis disorders, or too many peroxisomes, inducing oxidative damage and promoting diseases such as cancer. We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to reactive oxygen species (ROS), ATM signaling activates ULK1 and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser141, which promotes PEX5 mono-ubiquitination at K209, and recognition of ubiquitinated PEX5 by the autophagy adapter protein p62, directing the autophagosome to peroxisomes to induce pexophagy. These data reveal an important new role for ATM in metabolism as a sensor of ROS that regulates pexophagy.

Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.

We report direct measurements of electrical transport through poly(dA)-poly(dT) and poly(dG)-poly(dC) DNA molecules containing identical base pairs. The observed experimental results suggest that electrical transport through DNA molecules occurs by polaron hopping. We have also investigated the effect of gate voltage on the current-voltage curve. It demonstrates the possibility of a DNA field-effect transistor operating at room temperature. Moreover, the gate-voltage dependent transport measurements show that poly(dA)-poly(dT) behaves as an n-type semiconductor, whereas poly(dG)-poly(dC) behaves as a p-type semiconductor.

Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signaling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by PEX19 and PEX5, respectively, and peroxisome-localized TSC functioned as a Rheb GAP to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, abrogated peroxisome localization, Rheb GAP activity, and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS and peroxisome-localization deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for TSC in Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms COMPETING FINANCIAL INTERESTSThe authors declare that they have no competing financial interests. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript responding to ROS at the peroxisome, and identify the peroxisome as a signaling organelle involved in regulation of mTORC1.Tuberous sclerosis complex (TSC) is a hereditary hamartoma syndrome caused by defects in either the TSC1 or TSC2 genes 1, 2 . The TSC tumor suppressor is a heterodimer comprised of tuberin (TSC2), a GTPase activating protein (GAP), and its activation partner hamartin (TSC1), which localizes the TSC tumor suppressor to endomembranes and protects TSC2 from proteasomal degradation 3,4 . TSC inhibits the activity of the small GTPase Rheb to repress mammalian target of rapamycin complex 1 (mTORC1) signaling, a negative regulator of autophagy [5][6][7][8][9][10][11][12] . mTORC1 is regulated by a variety of cellular stimuli including amino acids, mitogens such as insulin, glucose, and energy stress [13][14][15] . In the case of amino acids, which do not signal through TSC-Rheb pathway 15 , mTORC1 activity is regulated by the Rag GTPases, which form the Ragulator complex that localizes mTORC1 to the late endosome or lysosome compartment of cells [13][14][15][16][17][18] . We recently reported that TSC functions in a signaling node downstream of ataxia telangiectasia mutated (ATM) to repress mTORC1 in response to reactive oxygen species (ROS) 19 . However, identification of the specific subcellular compartment(s) in which the TSC tumor suppressor functions to regulate mTORC1 in response to ROS has heretofore remained elusive.Peroxisomes, carry out key metabolic functions in the cell including β-oxidation of fatty acids, and are a major source of cellular ROS 20,21 . Like mitochondria, peroxisomes are autonomously replicating organelles. Peroxisome biogenesis requires peroxin (PEX) proteins, which are essential for assembly of functional peroxisomes 22 . Specific PEX pro...

We have observed unusual ferromagnetic properties in single-crystalline CoSi nanowire ensemble, in marked contrast to the diamagnetic CoSi in bulk. High-density freestanding CoSi nanowires with B20 crystal structure are synthesized by a vapor-transport-based method. The reaction of cobalt chloride precursor with a Si substrate produces high-aspect-ratio CoSi nanowires. The high-resolution transmission electron microscopy and electron diffraction studies reveal superlattice structure in CoSi nanowires with twice the lattice parameter of simple cubic CoSi lattice. The zero-field-cooled and field-cooled (ZFC-FC) measurements from the nanowire ensemble show freezing of the disordered surface spins at low temperatures. The magnetoresistance (MR) measurements of single nanowire devices show a negative MR whose magnitude gets larger at lower temperatures.

The review demonstrates accumulating evidence supporting health behavioral effects in reducing the risk of cognitive decline and dementia. Results indicate potential benefits of healthy lifestyles in protecting cognitive health in later life.

Background/Aims: Depending on the specific definition, acute kidney injury (AKI) occurs in 7–40% of patients undergoing cardiac surgery. Even small changes in serum creatinine (SCr) levels are associated with increased mortality after cardiac surgery. However, there are no current methods for preventing AKI after cardiac surgery. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in various experimental models. In this pilot trial, we evaluated the effectiveness of EPO in the prevention of AKI after coronary artery bypass grafting (CABG). Methods: 71 patients scheduled for elective CABG randomly received either 300 U/kg of EPO or saline intravenously before surgery. AKI was defined as a 50% increase in SCr levels over baseline within the first 5 postoperative days. Estimated glomerular filtration rate (eGFR) was calculated from the Cockcroft-Gault equation. Results: Of 71 patients, 13 developed postoperative AKI: 3 of the 36 patients in the EPO group (8%) and 10 of the 35 patients in the placebo group (29%; p = 0.035). The increase in postoperative SCr concentration and the decline in postoperative eGFR were significantly lower in the EPO group than in the placebo group. Conclusions: In our small, pilot trial, prophylactic administration of EPO prevents AKI and improves postoperative renal function. These data are preliminary and require confirmation in a larger clinical trial.