SUMMARY The sirtuin gene family (SIRT) is hypothesized to regulate the aging process and play a role in cellular repair. This work demonstrates that SIRT3−/− mouse embryonic fibroblasts (MEFs) exhibit abnormal mitochondrial physiology as well as increases in stress-induced superoxide levels and genomic instability. Expression of a single oncogene (Myc or Ras) in SIRT3−/− MEFs results in in vitro transformation and altered intracellular metabolism. Superoxide dismutase prevents transformation by a single oncogene in SIRT3−/− MEFs and reverses the tumor permissive phenotype as well as stress-induced genomic instability. In addition, SIRT3−/− mice develop ER/PR-positive mammary tumors. Finally, human breast and other human cancer specimens exhibit reduced SIRT3 levels. These results identify SIRT3 as a genomically expressed, mitochondrial localized tumor suppressor.

Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3−/− livers at 3 months of age. Livers of Sirt3−/− mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Re-introduction of wild-type, but not deacetylation null Sirt3, into Sirt3−/− MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSODK122-R), increased MnSOD activity when expressed in MnSOD−/− MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3−/− MEFs with lenti-MnSODK122-R inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3−/− livers and these irradiated livers displayed significant IR-induced cell damage and micro-vacuolization in their hepatocytes.

Summary Members of sirtuin family regulate multiple critical biological processes, yet their role in carcinogenesis remains controversial. To investigate the physiological functions of SIRT2 in development and tumorigenesis, we disrupted Sirt2 in mice. We demonstrated that SIRT2 regulates the anaphase-promoting complex/cyclosome activity through deacetylation of its co-activators, APCCDH1 and CDC20. SIRT2 deficiency caused increased levels of mitotic regulators, including Aurora-A and -B that direct centrosome amplification, aneuploidy, and mitotic cell death. Sirt2-deficient mice develop gender-specific tumorigenesis, with females primarily developing mammary tumors, and males developing more hepatocellular carcinoma (HCC). Human breast cancers and HCC samples exhibited reduced SIRT2 levels compared with normal tissues. These data demonstrate that SIRT2 is a tumor suppressor through its role in regulating mitosis and genome integrity.

Colloidal AuNPs show potential as a blood-pool agent for x-ray CT imaging.

Behçet disease is a chronic, relapsing, systemic disorder of unknown etiology, characterized by recurrent oral and genital ulcers, uveitis, and other clinical manifestations in multiple organ systems. Although the diagnosis is made on the basis of the combination of typical clinical symptoms, radiologic findings of Behçet disease show characteristic features of its involvement in the gastrointestinal, neurologic, cardiovascular, and thoracic organ systems. In the gastrointestinal tract, Behçet disease may produce various types of ulcers in the esophagus, stomach, and small and large intestines, as well as deeply penetrating ulcerations in the ileocecal region, with frequently accompanying enteric fistulas. Neurologic involvement includes typical and atypical parenchymal neurobehcet disease, dural sinus thrombosis, cerebral arterial aneurysm, occlusion, dissection, and meningitis. Vascular involvement is divided into three subsets including venous occlusion, arterial occlusion, and arterial aneurysm. Cardiac manifestations include intracardiac thrombus, endomyocardial fibrosis, periaortic pseudoaneurysm, and rupture of the sinus of Valsalva. Manifestations of Behçet disease in the thorax include pulmonary arterial aneurysm, pulmonary arterial thromboembolism, thrombosis in the superior vena cava, pulmonary infarction, hemorrhage, and vasculitis of the pleura and pericardium. These various manifestations of Behçet disease respond to steroid treatment; however, one of the characteristics of Behçet disease is the high rate of complications and recurrence after surgery. Familiarity with its various radiologic and clinical characteristics is essential in making an accurate early diagnosis and for prompt treatment of patients with Behçet disease.

Pyruvate dehydrogenase E1 alpha (PDHE1α or PDHA1) is the first component enzyme of the pyruvate dehydrogenase (PDH) complex (PDC) that transforms pyruvate, via pyruvate decarboxylation, into acetyl-CoA that is subsequently used by both the citric acid cycle and oxidative phosphorylation to generate ATP. As such, PDH links glycolysis and oxidative phosphorylation in normal as well as cancer cells. Herein we report that SIRT3 interacts with PDHA1 and directs its enzymatic activity via changes in protein acetylation. SIRT3 deacetylates PDHA1 lysine 321 (K321) and a PDHA1 mutant, mimicking a deacetylated lysine (PDHA1K321R) increases in PDH activity, as compared to the K321 acetylation mimic (PDHA1K321Q) or wild-type PDHA1. Finally, PDHA1K321Q exhibited a more transformed in vitro cellular phenotype as compared to PDHA1K321R. These results suggest that the acetylation of PDHA1 provides another layer of enzymatic regulation, in addition to phosphorylation, involving a reversible acetyl-lysine suggesting that the acetylome, as well as the kinome, links glycolysis to respiration.

A fundamental observation in biology is that mitochondrial function, as measured by increased reactive oxygen species (ROS), changes significantly with age, suggesting a potential mechanistic link between the cellular processes governing longevity and mitochondrial metabolism homeostasis. In addition, it is well established that altered ROS levels are observed in multiple age-related illnesses including carcinogenesis, neurodegenerative, fatty liver, insulin resistance, and cardiac disease, to name just a few. Manganese superoxide dismutase (MnSOD) is the primary mitochondrial ROS scavenging enzyme that converts superoxide to hydrogen peroxide, which is subsequently converted to water by catalase and other peroxidases. It has recently been shown that MnSOD enzymatic activity is regulated by the reversible acetylation of specific, evolutionarily conserved lysine(s) in the protein. These results, suggest for the first time, that the mitochondria contain bidirectional post-translational signaling networks, similar to that observed in the cytoplasm and nucleus, and that changes in lysine acetylation alter MnSOD enzymatic activity. In addition, these new results demonstrate that the mitochondrial anti-aging or fidelity / sensing protein, SIRT3, responds to changes in mitochondrial nutrient and/or redox status to alter the enzymatic activity of specific downstream targets, including MnSOD that adjusts and/or maintains ROS levels as well as metabolic homeostatic poise.

Narcissists, who seek keenly to self-enhance, strive to positively distinguish themselves. Might they therefore be inclined to purchase consumer products that enable them to do so? Study 1 found that narcissism, but not self-esteem, predicted dispositions to purchase products for the purpose of promoting personal uniqueness. Studies 2 and 3 found that narcissism predicted greater interest in exclusive, customizable, and personalizable products. Study 3 also found participants higher in narcissism regarded their prized possessions as less likely to be owned by others. Finally, Studies 3 and 4 found that interest in a hypothetical product, respectively, to be bought either for oneself or someone else, covaried with an experimental manipulation of product exclusivity and scarcity, but principally when levels of narcissism were high. Our findings illustrate the impact of narcissism on consumer preferences and support an agentic interpretation of narcissistic self-enhancement.