The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.

Aims: The collagen-stimulated generation of reactive oxygen species (ROS) regulates signal transduction in platelets, although the mechanism is unclear. The major targets of ROS include protein tyrosine phosphatases (PTPs). ROSmediated oxidation of the active cysteine site in PTPs abrogates the PTP catalytic activity. The aim of this study was to elucidate whether collagen-induced ROS generation leads to PTP oxidation, which promotes platelet stimulation. Results: SH2 domain-containing PTP-2 (SHP-2) is oxidized in platelets by ROS produced upon collagen stimulation. The oxidative inactivation of SHP-2 leads to the enhanced tyrosine phosphorylation of spleen tyrosine kinase (Syk), Vav1, and Bruton's tyrosine kinase (Btk) in the linker for the activation of T cells signaling complex, which promotes the tyrosine phosphorylation-mediated activation of phospholipase Cc2 (PLCc2). Moreover, we found that, relative to wild-type platelets, platelets derived from glutathione peroxidase 1 (GPx1)/catalase double-deficient mice showed enhanced cellular ROS levels, oxidative inactivation of SHP-2, and tyrosine phosphorylation of Syk, Vav1, Btk, and PLCc2 in response to collagen, which subsequently led to increased intracellular calcium levels, degranulation, and integrin a IIb b 3 activation. Consistent with these findings, GPx1/catalase double-deficiency accelerated the thrombotic response in FeCl 3 -injured carotid arteries. Innovation: The present study is the first to demonstrate that SHP-2 is targeted by ROS produced in collagen-stimulated platelets and suggests that a novel mechanism for the regulation of platelet activation by ROS is due to oxidative inactivation of SHP-2. Conclusion: We conclude that collagen-induced ROS production leads to SHP-2 oxidation, which promotes platelet activation by upregulating tyrosine phosphorylation-based signal transduction. Antioxid. Redox Signal. 20, 2528Signal. 20, -2540

Background and ObjectivesRecent studies have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF)-associated hospitalization and mortality in patients with diabetes. However, it is not clear whether SGLT2 inhibitors have a cardiovascular benefit in patients without diabetes. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role in HF without diabetes.MethodsCardiomyopathy was induced in C57BL/6J mice using intraperitoneal injection of doxorubicin (Dox). Mice with HF were fed a normal chow diet (NCD) or an NCD containing 0.03% EMPA. Then we analyzed their phenotypes and performed in vitro experiments to reveal underlying mechanisms of the EMPA's effects.ResultsMice fed NCD with EMPA showed improved heart function and reduced fibrosis. In vitro studies showed similar results. Phloridzin, a non-specific SGLT inhibitor, did not show any protective effect against Dox toxicity in H9C2 cells. SGLT2 inhibitor can cause increase in blood ketone levels. Beta hydroxybutyrate (βOHB), which is well known ketone body associated with SGLT2 inhibitor, showed a protective effect against Dox in H9C2 cells and in Dox-treated mice. These results suggest elevating βOHB might be a convincing mechanism for the protective effects of SGLT2 inhibitor.ConclusionsSGLT2 inhibitors have a protective effect in Dox-induced HF in mice. This implied that SGLT2 inhibitor therapy could be a good treatment strategy even in HF patients without diabetes.

It is not easy to achieve secure key establishment in wireless sensor networks without public key cryptography. Many key management protocols have been proposed for the purpose. Among them, LEAP is a simple and elegant protocol that establishes multi-level keys in an efficient way, but its security mainly relies on that of a single initialization key. Though it is assumed that the initial deployment phase is secure and the key is erased from sensor nodes after the initialization in LEAP, the assumption could not be viable for two reasons. First, the same key should be used again for node addition after the initialization phase whereas the new node can be captured before removing the key. Second, the initial deployment of dense networks may not take short as LEAP expected in many cases. This paper rethinks the security of LEAP and proposes a more secure scheme with a new notion of probabilistic time intervals. Rather we localize the impact of key compromise within the time intervals.