A major cause of cell death caused by genotoxic stress is thought to be due to the depletion of NAD(+) from the nucleus and the cytoplasm. Here we show that NAD(+) levels in mitochondria remain at physiological levels following genotoxic stress and can maintain cell viability even when nuclear and cytoplasmic pools of NAD(+) are depleted. Rodents fasted for 48 hr show increased levels of the NAD(+) biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD(+). Increased Nampt provides protection against cell death and requires an intact mitochondrial NAD(+) salvage pathway as well as the mitochondrial NAD(+)-dependent deacetylases SIRT3 and SIRT4. We discuss the relevance of these findings to understanding how nutrition modulates physiology and to the evolution of apoptosis.

Carbon nanotube thin-film transistors are expected to enable the fabrication of high-performance, flexible and transparent devices using relatively simple techniques. However, as-grown nanotube networks usually contain both metallic and semiconducting nanotubes, which leads to a trade-off between charge-carrier mobility (which increases with greater metallic tube content) and on/off ratio (which decreases). Many approaches to separating metallic nanotubes from semiconducting nanotubes have been investigated, but most lead to contamination and shortening of the nanotubes, thus reducing performance. Here, we report the fabrication of high-performance thin-film transistors and integrated circuits on flexible and transparent substrates using floating-catalyst chemical vapour deposition followed by a simple gas-phase filtration and transfer process. The resulting nanotube network has a well-controlled density and a unique morphology, consisting of long (~10 µm) nanotubes connected by low-resistance Y-shaped junctions. The transistors simultaneously demonstrate a mobility of 35 cm(2) V(-1) s(-1) and an on/off ratio of 6 × 10(6). We also demonstrate flexible integrated circuits, including a 21-stage ring oscillator and master-slave delay flip-flops that are capable of sequential logic. Our fabrication procedure should prove to be scalable, for example, by using high-throughput printing techniques.

Skeletal and cardiac muscle depend on high turnover of ATP made by mitochondria in order to contract efficiently. The transcriptional coactivator PGC-1alpha has been shown to function as a major regulator of mitochondrial biogenesis and respiration in both skeletal and cardiac muscle, but this has been based only on gain-of-function studies. Using genetic knockout mice, we show here that, while PGC-1alpha KO mice appear to retain normal mitochondrial volume in both muscle beds, expression of genes of oxidative phosphorylation is markedly blunted. Hearts from these mice have reduced mitochondrial enzymatic activities and decreased levels of ATP. Importantly, isolated hearts lacking PGC-1alpha have a diminished ability to increase work output in response to chemical or electrical stimulation. As mice lacking PGC-1alpha age, cardiac dysfunction becomes evident in vivo. These data indicate that PGC-1alpha is vital for the heart to meet increased demands for ATP and work in response to physiological stimuli.

Background-The serine-threonine kinase Akt is activated by several ligand-receptor systems previously shown to be cardioprotective. Akt activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role in cardiac dysfunction or infarction, however, remains unclear. Methods and Results-We examined the effects of a constitutively active Akt mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. In vivo gene transfer of myr-Akt reduced infarct size by 64% and the number of apoptotic cells by 84% (PϽ0.005 for each). Ischemia-reperfusion injury decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise and fall (ϩdP/dt and ϪdP/dt). Akt activation restored regional wall thickening and ϩdP/dt and ϪdP/dt to levels seen in sham-operated rats. To better understand this benefit, we examined the effects of myr-Akt on hypoxic cardiomyocyte dysfunction in vitro. myr-Akt prevented hypoxia-induced abnormalities in cardiomyocyte calcium transients and shortening. Akt activation also enhanced sarcolemmal expression of Glut-4 in vivo and increased glucose uptake in vitro to the level seen with insulin treatment. Conclusions-Akt activation exerts a powerful cardioprotective effect after transient ischemia that probably reflects its ability to both inhibit cardiomyocyte death and improve function of surviving cardiomyocytes. Akt may represent an important nodal target for therapy in ischemic and other heart disease.